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| Open AccessGPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis
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
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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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Article
| Open AccessHuman Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments
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
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Article
| Open Accessγδ T cells control humoral immune response by inducing T follicular helper cell differentiation
Many immune functions have been reported for γδ T cells, including the regulation of antibody responses. Here the authors show that CXCR5+ γδ T cells release Wnt ligands to initiate the T follicular helper cell differentiation program and promote antibody production.
- Rafael M. Rezende
- , Amanda J. Lanser
- & Howard L. Weiner
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Article
| Open AccessEnhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks
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
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Article
| 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 AccessDNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.
- Lara Kular
- , Yun Liu
- & Maja Jagodic
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Article
| Open AccessTestosterone is an endogenous regulator of BAFF and splenic B cell number
Testosterone deficiency is associated with autoimmunity and increased B cell numbers, but the underlying mechanism is unclear. Here the authors show that testosterone may modulate the production of B cell survival factor BAFF by fibroblastic reticular cells via regulation of splenic neurotransmitter levels.
- Anna S. Wilhelmson
- , Marta Lantero Rodriguez
- & Åsa Tivesten
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Article
| Open AccessA20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation
As resident macrophages of the brain, microglia are important for neuroinflammatory responses. This work shows that nuclear factor kappa B regulatory protein A20 is important for microglia activation and regulation during inflammation of the central nervous system.
- Sofie Voet
- , Conor Mc Guire
- & Geert van Loo
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Article
| Open AccessA whole-genome sequence study identifies genetic risk factors for neuromyelitis optica
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
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Article
| Open AccessA loop region of BAFF controls B cell survival and regulates recognition by different inhibitors
BAFF is an important cytokine for B cell survival, and is a therapeutic target for autoimmune disorders. Here the authors show that a 'flap' region of BAFF converts BAFFR binding events into survival signals and, with structural data, that this ‘flap’ differentially modulates binding of drugs such as belimumab or atacicept.
- Michele Vigolo
- , Melissa G. Chambers
- & Pascal Schneider
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Article
| Open AccessA non-conserved amino acid variant regulates differential signalling between human and mouse CD28
CD28 transmits co-stimulatory signals for the activation of both mouse and human T cells, but in vivo hyperactivation of CD28 has opposite effects on system immunity. Here, the authors show that a single amino acid difference between mouse and human CD28 dictates this function distinction via differential recruitment of Nck.
- Nicla Porciello
- , Paola Grazioli
- & Loretta Tuosto
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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 AccessT cells specific for post-translational modifications escape intrathymic tolerance induction
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
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Article
| Open AccessHypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease
B cells are important for antigen presentation and antibody production in humoral immunity, but are also increasingly recognized for their immune regulatory functions. Here the authors show that HIF-1α, a hypoxia-induced transcription factor, is important for controlling IL-10 induction in and immune-suppressive activity of B cells.
- Xianyi Meng
- , Bettina Grötsch
- & Aline Bozec
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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 AccessMafB is a critical regulator of complement component C1q
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
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| Open AccessIL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease
IL-12p35 is common to IL-35 and IL-12, which have opposing effects on inflammation. Here the authors show that the IL-12p35 subunit induces regulatory B cells and can be used therapeutically to limit autoimmune uveitis in mice.
- Ivy M. Dambuza
- , Chang He
- & Charles E. Egwuagu
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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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Article
| Open AccessBCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases
BCATs catabolize leucine and other BCAAs. Here the authors show that BCAA metabolism affects the broken Krebs cycle, reprogramming macrophages to be less proinflammatory, and show that BCAT1 inhibitor ERG240 can treat arthritis in mice and glomerulonephritis in rats.
- Adonia E. Papathanassiu
- , Jeong-Hun Ko
- & Jacques Behmoaras
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Article
| Open AccessMicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis
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
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Article
| Open AccessTWEAK mediates inflammation in experimental atopic dermatitis and psoriasis
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
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Article
| Open AccessAssociation between a common immunoglobulin heavy chain allele and rheumatic heart disease risk in Oceania
Rheumatic heart disease (RHD) is a chronic auto-inflammatory reaction to group A streptococcal infection, and frequently occurs in individuals from the South Pacific. This study finds a novel association between an immunoglobulin heavy chain allele and risk of RHD in Pacific Islanders and South Asians.
- Tom Parks
- , Mariana M. Mirabel
- & Brenton Ward
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Article
| 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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Article
| Open AccessMonocyte-derived inflammatory Langerhans cells and dermal dendritic cells mediate psoriasis-like inflammation
Imiquimod exacerbates IL-23-induced skin inflammation and models psoriasis in mice. Here the authors show that this pathology is not dependent on resident dendritic cells, but on CCR6-induced immigration of monocyte-derived cells.
- Tej Pratap Singh
- , Howard H. Zhang
- & Joshua M. Farber
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Article
| Open AccessThe ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity
Hrd1 is an E3 ubiquitin ligase involved in ER-associated degradation and MHC I turnover. Here the authors use T-cell-specific ko mice and a mouse model of multiple sclerosis to show that Hrd1 also drives pro-inflammatory T helper cell responses and contributes to pathogenesis of autoimmune disease.
- Yuanming Xu
- , Fang Zhao
- & Deyu Fang
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| Open AccessTreatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells
Evidence of how functional Bregs develop in vivo has been lacking. Here the authors show that proB cells exposed in vivoto CpG differentiate into distinct Breg subsets that inhibit autoimmunity by arresting T cells in the lymph nodes via CCL19 and by producing IL-10 at the site of immunopathology.
- Sarantis Korniotis
- , Christophe Gras
- & Flora Zavala
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Article
| Open AccessAlterations of the human gut microbiome in multiple sclerosis
The gut microbiome has been implicated in several autoimmune disorders. Here, the authors study the gut microbiome of patients with multiple sclerosis, and find correlations between altered abundance of certain gut microorganisms and changes in expression of immune defence genes.
- Sushrut Jangi
- , Roopali Gandhi
- & Howard L. Weiner
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Article
| Open AccessJoint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes
Rheumatoid arthritis is an inflammatory disease that selectively affects different joints. Here the authors show that gene expression and DNA methylation patterns of fibroblast-like synoviocytes differ between hip and knee joints in patients with RA, thus providing epigenetic and transcriptomic evidence for this anatomic selectivity of inflammation.
- Rizi Ai
- , Deepa Hammaker
- & Wei Wang
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Article
| Open AccessNFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells
Regulatory B cells are important for preventing skin autoimmunity. Here the authors show that NFATc1 suppresses IL-10 transcription in regulatory B cells, and inhibiting NFATc1 decreases immunopathology in a mouse model of imiquimod-induced skin inflammation.
- Hani Alrefai
- , Khalid Muhammad
- & Edgar Serfling
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Article
| Open AccessGut environment-induced intraepithelial autoreactive CD4+ T cells suppress central nervous system autoimmunity via LAG-3
Experimental autoimmune encephalomyelitis (EAE) involves inflammatory cell infiltration into the central nervous system (CNS) and models the human disease multiple sclerosis. Here the authors show that transferred CD4+ gut intraepithelial lymphocytes can migrate into the CNS and inhibit inflammation in recipient mice with EAE.
- Atsushi Kadowaki
- , Sachiko Miyake
- & Takashi Yamamura
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| Open AccessExperimental priming of encephalitogenic Th1/Th17 cells requires pertussis toxin-driven IL-1β production by myeloid cells
Pertussis toxin enhances the induction of autoreactive T cells in mouse models of autoimmunity. Here the authors show that stimulation of IL-1β production in myeloid cells by pertussis toxin is necessary to prime pathogenic Th1/Th17 cells in experimental autoimmune encephalopathy.
- Francesca Ronchi
- , Camilla Basso
- & Federica Sallusto
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Article
| Open AccessGeneration of stem cell-derived β-cells from patients with type 1 diabetes
Pancreatic β cells can be generated from pluripotent stem cells. Here, the authors show that human induced pluripotent stem cells from patients with type 1 diabetes can be differentiated into β-like cells that have no detectable differences compared with cells from non-diabetic individuals.
- Jeffrey R. Millman
- , Chunhui Xie
- & Douglas A. Melton
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| Open AccessSex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator
Males are less susceptible to autoimmune diseases due to immunomodulatory effects of androgen. Here the authors show that androgen receptor upregulates Aire and Aire-dependent transcription in the thymic epithelium, and that Aire is required for androgen-mediated suppression of experimental autoimmune encephalitis.
- Meng-Lei Zhu
- , Pearl Bakhru
- & Maureen A. Su
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Article
| Open AccessSialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis
Post-translational modifications, such as glycosylation and sialylation, are thought to confer disease modifying effects on autoimmune-associated antibodies, including anti-citrullinated protein antibodies in rheumatoid arthritis. Here the authors show that sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis in mice.
- Yuhsuke Ohmi
- , Wataru Ise
- & Koichi Furukawa
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Article
| Open AccessKappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination
Current treatments of multiple sclerosis are aimed at immunosuppression. Here the authors show that kappa opioid receptor is important for oligodendrocyte differentiation and myelination and the receptor agonists are protective in a mouse model of multiple sclerosis.
- Changsheng Du
- , Yanhui Duan
- & Xin Xie
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Article
| Open AccessType 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice
Type 1 diabetes is associated with the loss of self-tolerance to the insulin-producing β-cells in the pancreas. Here the authors show that vaccination with insulin mimetopes can induce human insulin-specific regulatory T cells to mediate tolerance in a humanized mouse model.
- Isabelle Serr
- , Rainer W. Fürst
- & Carolin Daniel
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Article
| Open AccessIncreased generation of Foxp3+ regulatory T cells by manipulating antigen presentation in the thymus
The degree of Treg self-antigen reactivity varies across experimental systems. Here the authors develop a new model of skin autoimmunity and show that the size of tissue-specific Treg pool in the thymus depends on AIRE, the availability of the tissue antigen, and its presentation by dendritic cells.
- Jiqiang Lin
- , Lu Yang
- & Juan J. Lafaille
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Article
| Open AccessLocal T/B cooperation in inflamed tissues is supported by T follicular helper-like cells
In secondary lymphoid organs T follicular helper (Tfh) cells help B cells to develop into memory B and plasma cells. Here, the authors show that inflamed lung becomes a reservoir of activated B cells with a germinal centre phenotype, and T cells that exhibit Tfh-like properties despite not expressing classical Tfh markers.
- Dana Vu Van
- , Katja C. Beier
- & Andreas Hutloff
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Article
| Open AccessIdentification of an allosteric binding site for RORγt inhibition
Upon the binding of small ligands, nuclear receptors regulate the transcription of genes that are associated with a number of disease mechanisms. Here, the authors report on a novel allosteric ligand binding site on the nuclear receptor RORγt.
- Marcel Scheepstra
- , Seppe Leysen
- & Luc Brunsveld
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Article
| Open AccessCapture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci
There is evidence that a proportion of the polymorphisms identified by genome-wide association studies lie in enchancer regions. Here the authors use Capture Hi-C to investigate the interaction with targets in autoimmune disease, showing interactions can be long range and cell-type specific.
- Paul Martin
- , Amanda McGovern
- & Steve Eyre
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Article
| Open AccessGenetic sharing and heritability of paediatric age of onset autoimmune diseases
Autoimmune diseases are genetically complex disorders that affect up to 10% of the Western population. Here Li et al. quantify the heritability of a range of autoimmune diseases in the largest paediatric cohort examined to date, illustrating that genetic and non-genetic components variably contribute to the susceptibility of each disease.
- Yun R. Li
- , Sihai D. Zhao
- & Hakon Hakonarson
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Article
| Open AccessEomesodermin-expressing T-helper cells are essential for chronic neuroinflammation
Eomesodermin is a master regulator of effector CD8+ T cells. Here the authors show that it also plays a critical role in pathogenic CD4+ cells in a mouse model of multiple sclerosis, and its inactivation ameliorates the chronic stage of the disease.
- Ben J. E. Raveney
- , Shinji Oki
- & Takashi Yamamura
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Article
| Open AccessAntibiotics in neonatal life increase murine susceptibility to experimental psoriasis
Commensal microbes are necessary for proper development of the immune system. Here Zanvit et al. show that neonatal antibiotics treatment causes long-term changes in the gut and skin microbiomes, and exacerbates immune-mediated skin pathology at adult age in mouse experimental models of psoriasis.
- Peter Zanvit
- , Joanne E. Konkel
- & WanJun Chen
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Article
| Open AccessCTRP6 is an endogenous complement regulator that can effectively treat induced arthritis
The complement system contributes to chronic inflammatory diseases. Here the authors show that CRTP6 suppresses the alternative complement pathway and reverses rheumatoid arthritis in a mouse model of the disease.
- Masanori A. Murayama
- , Shigeru Kakuta
- & Yoichiro Iwakura
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Article
| Open AccessDesialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
Immune thrombocytopenia (ITP) is caused by autoantibody-mediated platelet clearance, but refractoriness to current immunomodulatory therapies is common. Here the authors show that desialylated platelets can be cleared via hepatic Ashwell–Morell receptor, a process that can be attenuated by sialidase inhibitors, suggesting a new therapy for ITP.
- June Li
- , Dianne E. van der Wal
- & Heyu Ni
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Article
| Open AccessMicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3
Peripherally derived regulatory T cells (pTreg) exhibit immunosuppressive capacity. Here, the authors show that microRNA-31 acting through inhibiting its direct target Gprc5a negatively regulates pTreggeneration and promotes the development of experimental autoimmune encephalomyelitis.
- Lingyun Zhang
- , Fang Ke
- & Honglin Wang
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Article
| Open AccessIL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2+Vγ6+γδ T cells
Control of γδ T-cell activation remains incompletely understood. Here the authors show that during autoimmune arthritis development αβ CD4+T cells recruit a subset of IL-17-producing γδ T cells to the joints, and that both components are essential to cause pathology in a mouse model of the disease.
- Aoi Akitsu
- , Harumichi Ishigame
- & Yoichiro Iwakura