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Article
| Open Access
B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4
The immune system is tolerized against the neuromyelitis optica autoantigen AQP4 by thymic B cells, which present their endogenous AQP4 to AQP4-reactive thymocytes.
- Ali Maisam Afzali
- , Lucy Nirschl
- & Thomas Korn
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Article |
Bone marrow plasma cells require P2RX4 to sense extracellular ATP
We demonstrate the role of the ligand-gated purinergic ion channel P2RX4 in maintaining mouse plasma cells in their bone marrow niche.
- Masaki Ishikawa
- , Zainul S. Hasanali
- & Avinash Bhandoola
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Article
| Open Access
Autoreactive T cells target peripheral nerves in Guillain–Barré syndrome
Autoreactive T cells that target myelin antigens in the peripheral nerves are present in patients with the demyelinating form of Guillain–Barré syndrome, and these T cells are likely to contribute to disease pathophysiology.
- L. Súkeníková
- , A. Mallone
- & D. Latorre
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Article
| Open Access
Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations
Analysis of a large ancient genome dataset shows that genetic risk for multiple sclerosis rose in steppe pastoralists, providing insight into how genetic ancestry from the Neolithic and Bronze Age has shaped modern immune responses.
- William Barrie
- , Yaoling Yang
- & Eske Willerslev
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Article |
Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease
A large fraction of patients with APS-1 and coeliac disease develop enamel dystrophy, characterized by the presence of autoantibodies against the enamel matrix, which are generated through the breakdown of either central (APS-1) or peripheral (coeliac) tolerance to a battery of ameloblast-sepecific proteins.
- Yael Gruper
- , Anette S. B. Wolff
- & Jakub Abramson
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Article |
Thymic mimetic cells function beyond self-tolerance
Multiomic analyses of mouse thymic epithelial cells identify several unconventional subsets that are mimetics of various populations of terminally differentiated parenchymal cells and provide insights into their development, molecular features and function.
- Tal Givony
- , Dena Leshkowitz
- & Jakub Abramson
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Article |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells
Lactate produced by dendritic cells (DCs) suppresses T-cell-mediated autoimmunity through a mechanism in which lactate activates HIF-1α–NDUFA4L2 signalling in DCs and thereby limits DC-mediated pro-inflammatory responses such as the development of encephalitogenic T cells.
- Liliana M. Sanmarco
- , Joseph M. Rone
- & Francisco J. Quintana
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Article |
Locus for severity implicates CNS resilience in progression of multiple sclerosis
A genome-wide association study including 22,389 cases of multiple sclerosis finds an association with disease progression at the DYSF–ZNF638 and DNM3–PIGC loci and identifies a potential of higher educational attainment in slowing disease progression.
- Adil Harroud
- , Pernilla Stridh
- & Kári Stefánsson
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Article |
PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens
A mouse model expressing T cell antigens in the skin epidermis is used to demonstrate that local self-tolerance is maintained by PD-1, which prevents terminal CD8 T cell differentiation, effector molecule secretion and access to antigen-expressing cells.
- Martina Damo
- , Noah I. Hornick
- & Nikhil S. Joshi
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Article |
Autoimmunity in Down’s syndrome via cytokines, CD4 T cells and CD11c+ B cells
An autoimmune-prone state of steady-state cytokinopathy, hyperactivated CD4 T cells and ongoing B cell activation contributes to a breach in immune tolerance in individuals with Down’s syndrome.
- Louise Malle
- , Roosheel S. Patel
- & Dusan Bogunovic
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Matters Arising |
Reply to: GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation
- Tao Xu
- , Zhen Qin
- & Sheng Ding
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Matters Arising |
GOT1 constrains TH17 cell differentiation, while promoting iTreg cell differentiation
- Wei Xu
- , Chirag H. Patel
- & Jonathan D. Powell
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Article |
Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides
A study shows that cross-reactivity of microbial antigens and self-antigens presented by HLA-B*27 may be important in the pathogenesis of diseases associated with HLA-B*27 and identifies the shared binding motif responsible.
- Xinbo Yang
- , Lee I. Garner
- & K. Christopher Garcia
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Article |
Identification of environmental factors that promote intestinal inflammation
The herbicide propyzamide increases inflammation in the small and large intestine, and the AHR–NF-κB–C/EBPβ signalling axis—which operates in T cells and dendritic cells to promote intestinal inflammation—is targeted by propyzamide.
- Liliana M. Sanmarco
- , Chun-Cheih Chao
- & Francisco J. Quintana
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Article |
ADAR1 mutation causes ZBP1-dependent immunopathology
The autoinflammatory pathology associated with alteration of the ZBD domain of the RNA-editing enzyme ADAR1 is driven by signalling that is dependent on the nucleotide sensor ZBP1.
- Nicholas W. Hubbard
- , Joshua M. Ames
- & Andrew Oberst
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Article |
Within-host evolution of a gut pathobiont facilitates liver translocation
Within-host evolution is a critical regulator of commensal pathogenicity that provides a unique source of stochasticity in the development and progression of microbiota-driven disease.
- Yi Yang
- , Mytien Nguyen
- & Noah W. Palm
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Article
| Open Access
TLR7 gain-of-function genetic variation causes human lupus
The missense TLR7Y264H gain-of-function genetic variation causes systemic lupus erythematosus in humans and mice.
- Grant J. Brown
- , Pablo F. Cañete
- & Carola G. Vinuesa
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The lung microbiome regulates brain autoimmunity
Work in experimental autoimmune models shows that the lung microbiome is linked to immune reactivity in the brain through a mechanism in which the balance of pulmonary microorganisms regulates the activation state of microglia.
- Leon Hosang
- , Roger Cugota Canals
- & Francesca Odoardi
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Article
| Open Access
Twin study reveals non-heritable immune perturbations in multiple sclerosis
In monozygotic twins discordant for multiple sclerosis, the influence of genetic predisposition and environmental factors is determined using matched-pair analyses.
- Florian Ingelfinger
- , Lisa Ann Gerdes
- & Burkhard Becher
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Article |
Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM
The identification of high-affinity molecular mimicry between the Epstein–Barr virus (EBV) transcription factor EBNA1 and the CNS protein GlialCAM provides a mechanistic link between multiple sclerosis and EBV.
- Tobias V. Lanz
- , R. Camille Brewer
- & William H. Robinson
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Article |
Anatomically distinct fibroblast subsets determine skin autoimmune patterns
Single-cell analyses of skin samples from patients with vitiligo and functional genetic experiments in vitiligo mouse models show that distinct fibroblast subsets drive the organ level lesion patterns in this autoimmune disease.
- Zijian Xu
- , Daoming Chen
- & Ting Chen
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Article |
Antigen-presenting innate lymphoid cells orchestrate neuroinflammation
A subset of inflammatory group 3 innate lymphoid cells, here termed iILC3s, infiltrate the central nervous system and promote neuroinflammation and disease progression in a mouse model of multiple sclerosis.
- John B. Grigg
- , Arthi Shanmugavadivu
- & Gregory F. Sonnenberg
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Article |
Diverse functional autoantibodies in patients with COVID-19
Rapid extracellular antigen profiling of a cohort of 194 individuals infected with SARS-CoV-2 uncovers diverse autoantibody responses that affect COVID-19 disease severity, progression and clinical and immunological characteristics.
- Eric Y. Wang
- , Tianyang Mao
- & Aaron M. Ring
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Article |
AIM2 in regulatory T cells restrains autoimmune diseases
The inflammasome receptor AIM2 acts independently of the inflammasome to reduce autoimmunity and stabilize regulatory T cells.
- Wei-Chun Chou
- , Zengli Guo
- & Jenny P.-Y. Ting
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Article |
Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes
A subpopulation of astrocytes characterized by the expression of LAMP1 and TRAIL limits inflammation in the central nervous system through a mechanism involving the microbiota-modulated expression of IFNγ in meningeal natural killer cells.
- Liliana M. Sanmarco
- , Michael A. Wheeler
- & Francisco J. Quintana
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Article |
ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies
An autoantibody found in a mouse model of atherosclerosis recognizses ALDH4A1, and infusion of the antibody delays plaque formation in mice.
- Cristina Lorenzo
- , Pilar Delgado
- & Almudena R. Ramiro
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Article |
Gut microorganisms act together to exacerbate inflammation in spinal cords
Germ-free mice co-colonized with two bacterial strains from the small intestinal flora showed increased susceptibility to experimental autoimmune encephalomyelitis, implicating the synergistic effects of these microorganisms in this mouse model of multiple sclerosis.
- Eiji Miyauchi
- , Seok-Won Kim
- & Hiroshi Ohno
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Article |
A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by Treg cells
Shared synteny guides loss-of-function analysis of human enhancer homologues in mice, identifying a distal enhancer at the autoimmune and allergic disease risk locus at chromosome 11q13.5 whose function in regulatory T cells provides a mechanistic basis for its role in disease.
- Rabab Nasrallah
- , Charlotte J. Imianowski
- & Rahul Roychoudhuri
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Article |
TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9
The interaction between TASL and SLC15A4 links endolysosomal Toll-like receptors to the transcription factor IRF5, providing a mechanistic explanation for the involvement of the complex in systemic lupus erythematosus.
- Leonhard X. Heinz
- , JangEun Lee
- & Giulio Superti-Furga
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Article |
Notch signalling drives synovial fibroblast identity and arthritis pathology
NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.
- Kevin Wei
- , Ilya Korsunsky
- & Michael B. Brenner
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Letter |
Analysis of the B cell receptor repertoire in six immune-mediated diseases
An analysis of the B cell receptor repertoire in six immune-mediated diseases reveals that there are substantial differences in clonality, isotype use, class switching and use of the IGHV genes between diseases.
- R. J. M. Bashford-Rogers
- , L. Bergamaschi
- & K. G. C. Smith
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Article |
UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity
The interaction of UNC93B1 with syntenin-1 facilitates the sorting of TLR7–UNC93B1 complexes into intraluminal vesicles of multivesicular bodies, and mutations in UNC93B1 that disrupt such interactions lead to enhanced TLR7 signalling and autoimmunity.
- Olivia Majer
- , Bo Liu
- & Gregory M. Barton
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Article |
Release from UNC93B1 reinforces the compartmentalized activation of select TLRs
The Toll-like receptor TLR9 is activated only after regulated release from its trafficking chaperone UNC93B1, which occurs within endosomes and is required for ligand binding and signal transduction.
- Olivia Majer
- , Bo Liu
- & Gregory M. Barton
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Article |
Opposing T cell responses in experimental autoimmune encephalomyelitis
Activated clonally expanded CD4+ T cells display specificity to the myelin peptide MOG, whereas clonally expanded CD8+ T cells depend on T cell receptor recognition of unrelated surrogate peptides and have a regulatory function.
- Naresha Saligrama
- , Fan Zhao
- & Mark M. Davis
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Letter |
Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice
In mice lacking PINK1, bacterial infection in the intestine results in mitochondrial antigen presentation and generation of CD8+ T cells, and infected mice develop motor impairments, suggesting that PINK1 suppresses autoimmunity.
- Diana Matheoud
- , Tyler Cannon
- & Michel Desjardins
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Letter |
Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity
Phenotypically, transcriptionally and metabolically diverse subsets of TH17 cells develop in a chronic autoimmune disease: one subset has inferred stemness features and low anabolic metabolism, while a reciprocal subset has higher metabolic activity that supports transdifferentiation into TH1 cells.
- Peer W. F. Karmaus
- , Xiang Chen
- & Hongbo Chi
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Letter |
The metabolite BH4 controls T cell proliferation in autoimmunity and cancer
Tetrahydrobiopterin (BH4) is an enzyme co-factor that is involved in the nervous system; it is shown here to also function in T cell activation and proliferation, with roles in autoimmunity, allergic inflammation and cancer.
- Shane J. F. Cronin
- , Corey Seehus
- & Josef M. Penninger
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Article |
T cells in patients with narcolepsy target self-antigens of hypocretin neurons
The detection of hypocretin-specific autoreactive CD4+ and CD8+ T cells in patients with narcolepsy reveals the autoimmune aetiology of this disorder.
- Daniela Latorre
- , Ulf Kallweit
- & Federica Sallusto
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Letter |
Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides
A sensitive T cell tracking assay reveals immunogenic activity of specific catabolized peptide fragments of insulin and their effects on T cell activity in lymph nodes, highlighting communication between pancreatic islets and lymphoid tissue.
- Xiaoxiao Wan
- , Bernd H. Zinselmeyer
- & Emil R. Unanue
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Article |
Genomic atlas of the human plasma proteome
A genetic atlas of the human plasma proteome, comprising 1,927 genetic associations with 1,478 proteins, identifies causes of disease and potential drug targets.
- Benjamin B. Sun
- , Joseph C. Maranville
- & Adam S. Butterworth
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Letter |
c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont
The transcription factor c-MAF is required for the generation of Helicobacter-specific regulatory T cells that selectively restrain pro-inflammatory TH17 cells; the absence of c-MAF in mouse regulatory T cells results in pathobiont-dependent inflammatory bowel disease.
- Mo Xu
- , Maria Pokrovskii
- & Dan R. Littman
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Letter |
Reversing SKI–SMAD4-mediated suppression is essential for TH17 cell differentiation
TGFβ signalling regulates T helper 17 (TH17) cell differentiation by reversing SKI–SMAD4-mediated suppression of RORγt, revealing a potential therapeutic target for treating TH17-related diseases.
- Song Zhang
- , Motoki Takaku
- & Yisong Y. Wan
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Letter |
Microglia-dependent synapse loss in type I interferon-mediated lupus
Abnormal behavioural phenotypes and synapse loss in the brain of lupus-prone mice are prevented by blocking type I interferon signalling, which is further shown to stimulate microglial phagocytosis of neuronal material in the brains of these mice.
- Allison R. Bialas
- , Jessy Presumey
- & Michael C. Carroll
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Letter |
Stability and function of regulatory T cells expressing the transcription factor T-bet
Regulatory T cells expressing the transcription factor T-bet selectively suppress TH1 and CD8 T cells, but not TH2 or TH17 activation and associated autoimmunity.
- Andrew G. Levine
- , Alejandra Mendoza
- & Alexander Y. Rudensky
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Letter |
Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells
The molecular mechanism of Goodpasture disease is modelled to mechanistically determine how a human leukocyte antigen (HLA) allele can exert its dominant protective effect in autoimmune disease.
- Joshua D. Ooi
- , Jan Petersen
- & A. Richard Kitching
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Letter |
Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis
The authors identify in patients with rheumatoid arthritis a pathogenic subset of CD4+ T cells that augments B cell responses within inflamed tissues.
- Deepak A. Rao
- , Michael F. Gurish
- & Michael B. Brenner
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Letter |
RETRACTED ARTICLE: Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells
Defects in LC3-associated phagocytosis in mice are shown to result in systemic lupus erythematosus-like disease; dying cells are engulfed but not degraded in LAP-deficient mice, resulting in increased serum levels of autoantibodies and inflammatory cytokines, and evidence of kidney disease.
- Jennifer Martinez
- , Larissa D. Cunha
- & Douglas R. Green
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Article |
Expanding antigen-specific regulatory networks to treat autoimmunity
Nanoparticles coated with autoantigenic peptides bound to MHC class II molecules suppress established autoimmune disease by inducing antigen-specific TR1-like regulatory T cells in mouse and humanized mouse models.
- Xavier Clemente-Casares
- , Jesus Blanco
- & Pere Santamaria
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Letter |
Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid
By investigating trafficking of autoreactive T cells into the CSF during experimental autoimmune encephalitis, the authors find that T cells enter the CSF from the leptomeninges, and that commuting between the leptomeninges and the CSF is regulated by integrin adhesive forces triggered by T-cell activation and/or chemokines.
- Christian Schläger
- , Henrike Körner
- & Alexander Flügel
AIRE relies on Z-DNA to flag gene targets for thymic T cell tolerization