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Article
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Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis
Although many autoimmune diseases are characterized by the presence of autoantibodies, complete characterisation of autoantibody repertoires is lacking. Here, the authors introduce an autoantigen-specific Fab profiling method to show that the autoantibody repertoire in rheumatoid arthritis is diverse yet dominated only by a few clones.
- Eva Maria Stork
- , Danique M. H. van Rijswijck
- & Albert Bondt
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Article
| Open Access
Senescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice
In their previous study, the researchers systematically revealed that endplate sclerosis is a significant aspect of spine degeneration or aging and a primary source of spinal pain. However, the underlying mechanisms of endplate sclerosis remained unclear. In their current report, it is shown that senescent cells accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging mouse models. The clearance of these senescent cells was found to restrain angiogenesis coupled with endplate sclerosis. Notably, macrophages were identified as undergoing senescence in the sclerotic endplates. The specific knockout of cdkn2a (p16) in macrophages abrogated LSI or aging-induced angiogenesis and sclerosis in the endplates. Moreover, both in vivo and in vitro studies indicated that IL-10 mediates the effects of senescent macrophages on angiogenesis and sclerosis in the endplates. Overall, these findings suggest that senescent macrophages orchestrate angiogenesis coupling with endplate sclerosis via the IL-10/pSTAT3 axis. This study enhances the understanding of the connection between immune senescence and endplate sclerosis and uncovers senescent macrophage-initiated endplate sclerosis as potential therapeutic targets for spinal degeneration.
- Yonggang Fan
- , Weixin Zhang
- & Shuangfei Ni
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Article
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Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation
Activation of the mechanistic target of rapamycin (mTOR) is important in the metabolic function of proinflammatory T cells in autoimmunity. Here the authors characterise how Rab4A is involved with CD98 and endosome recycling which subsequently affects mTOR activation, autoimmunity and T cell expansion.
- Nick Huang
- , Thomas Winans
- & Andras Perl
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Article
| Open Access
Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis
The TAM tyrosine kinases, Axl and MerTK, have been implicated in rheumatoid arthritis (RA). Here, using a synovial tissue bioresource of patients with RA, the authors describe how Axl and MerTK expression and function are linked to synovial histopathology, disease activity, and therapeutic intervention with IL-6 inhibitors.
- Alessandra Nerviani
- , Marie-Astrid Boutet
- & Costantino Pitzalis
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Article
| Open Access
Dynamic similarity and the peculiar allometry of maximum running speed
How fast can animals run? Here, the authors show that maximum running speed is limited by different musculoskeletal constraints across animal size: kinetic energy capacity in small animals, and work capacity in large animals.
- David Labonte
- , Peter J. Bishop
- & Christofer J. Clemente
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Article
| Open Access
Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development
Fine-mapping has previously implicated the non-coding single nucleotide polymorphism rs117701653 as a risk variant for rheumatoid arthritis and type 1 diabetes, however its function remained unclear. Here the authors show that this variant decreases binding of the inhibitory factor SMCHD1 to enhance expression of ICOS, promoting development of potentially pathogenic T peripheral helper cells.
- Taehyeung Kim
- , Marta Martínez-Bonet
- & Peter A. Nigrovic
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Article
| Open Access
Single-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis
Patients undergoing treatment with PD-1 blockade can experience inflammatory arthritis as an adverse event. Here, the authors use single-cell RNA sequencing to identify IL1Bhi macrophages in PD-1-inhibitor-induced arthritis, but not rheumatoid arthritis.
- Ziyue Zhou
- , Xiaoxiang Zhou
- & Xuan Zhang
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Article
| Open Access
MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution
Three-dimensional analysis of the intact bone marrow within whole long bones remains very challenging. Here, the authors present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur.
- Till Fabian Mertens
- , Alina Tabea Liebheit
- & Anja Erika Hauser
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Article
| Open Access
A landscape of gene expression regulation for synovium in arthritis
Hundreds of arthritis-associated genetic variants have been identified but in most cases their functions remain unknown. Here the authors develop a resource to reveal the effects of variants on gene expression in human synovium, and identify arthritis-related genes.
- Feng Jiang
- , Shou-Ye Hu
- & Tie-Lin Yang
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Article
| Open Access
Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission
Immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are characterised by relapsing-remitting flares, which are difficult to study due to their unpredictable nature. Here the authors use an experimental model of immunomodulatory drug cessation in RA patients combined with multi-omic analysis of circulating leukocytes to characterise the immune response for those with arthritis flare versus drug-free remission.
- Kenneth F. Baker
- , David McDonald
- & John D. Isaacs
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Article
| Open Access
Eosinophils preserve bone homeostasis by inhibiting excessive osteoclast formation and activity via eosinophil peroxidase
Eosinophils are traditional immune effectors involved in tissue homeostasis. In this study, eosinophils emerge as key regulators of bone homeostasis by interacting with osteoclasts, inhibiting their differentiation and pathological bone loss.
- Darja Andreev
- , Katerina Kachler
- & Aline Bozec
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Article
| Open Access
5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis
There is a strong need for the development of effective and safe disease-modifying osteoarthritis drugs. Here, the authors show that 5-ASA, an anti-inflammatory drug used for ulcerative colitis, shows promise in treating osteoarthritis in mice by improving cartilage and reducing inflammation even when administered at late stages of disease.
- Jihee Kim
- , Gina Ryu
- & Soo Young Lee
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Article
| Open Access
GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
Here, the authors identify six risk SNPs for systemic sclerosis by performing GWAS on Japanese patients and meta-analyzing Japanese and European GWAS datasets. Downstream analyses indicate that B cells contribute to pathogenesis.
- Yuki Ishikawa
- , Nao Tanaka
- & Chikashi Terao
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Article
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CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses
Calmodulin-dependent kinase 4 (CaMK4) has been implicated in humoral immunity. Here, the authors demonstrate that CaMK4 expression controls the differentiation of T follicular helper cells, leading to the expansion of pathogenic B cells in systemic lupus erythematosus.
- Marc Scherlinger
- , Hao Li
- & George C. Tsokos
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Article
| Open Access
Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice
Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic autoimmunity. Here, the authors demonstrate that a palmitoylation cycle controlled by PPT1 and DHHC3 regulates TLR9 trafficking to endosomes, signalling and systemic autoimmunity in mice.
- Hai Ni
- , Yinuo Wang
- & Jijun Zhao
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Article
| Open Access
Functional and analytical recapitulation of osteoclast biology on demineralized bone paper
Here, authors report demineralized bone paper-based in vitro osteogenic culture and assay platforms that replicate essential bone tissue complexity, osteoclast processes, and drug responses with high fidelity and predictive power.
- Yongkuk Park
- , Tadatoshi Sato
- & Jungwoo Lee
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Article
| Open Access
Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis
The presence of antibodies to citrullinated protein antigens (ACPA) in peripheral blood represents a risk a state that is ‘at-risk’ for subsequent development of rheumatoid arthritis (RA). Here authors compare multiple molecular and immunological parameters in individuals who are ACPA positive without inflammatory arthritis, ACPA negative controls and patients diagnosed with ACPA positive early-stage RA to conclude that complex immunopathological processes are present in an ACPA positive state which may be targeted by future preventive approaches for RA.
- Eddie A. James
- , V. Michael Holers
- & Kevin D. Deane
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| Open Access
Mechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks
The 24-hour circadian clocks in cartilage and intervertebral disc play key roles in regulating tissue physiology, yet how they are reset on a daily basis remains elusive. Here the authors show that daily patterns of mechanical loading and associated changes in osmolarity provide a tissue-type specific entrainment time cue for these skeletal clocks.
- Michal Dudek
- , Dharshika R. J. Pathiranage
- & Qing-Jun Meng
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Antigen presentation by B cells enables epitope spreading across an MHC barrier
Increasing evidence suggests that antigen presentation by B cells is critical to the initiation of autoimmunity. Here, the authors demonstrate that tolerance breakdown is initiated outside of germinal centres and that B cells can directly instruct T cells to break tolerance and propagate autoimmune responses.
- Cecilia Fahlquist-Hagert
- , Thomas R. Wittenborn
- & Søren E. Degn
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Article
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ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
Raynaud’s phenomenon is a common vasospastic disorder, but the genetic origins of the condition are not well understood. Here, the authors find common genetic variants associated with Raynaud’s phenomenon, and find genes putatively involved in the disorder.
- Sylvia Hartmann
- , Summaira Yasmeen
- & Claudia Langenberg
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| Open Access
Single-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis
Autoimmune vasculitis can be heterogeneous in terms of immune cell involvement. Here the authors use a single cell transcriptomics approach to characterise a group of microscopic polyangiitis patients that could be split into two groups typified by monocyte or Interferon associated gene expression.
- Masayuki Nishide
- , Kei Nishimura
- & Atsushi Kumanogoh
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| Open Access
MYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling
Age is the greatest risk factor for osteoarthritis (OA) and chondrocyte senescence is an important cellular event that contributes to OA development. This study shows that clathrin-mediated endocytosis and activation of Notch signaling promotes articular chondrocyte senescence and OA development, which is negatively regulated by myosin light chain 3 (MYL3).
- He Cao
- , Panpan Yang
- & Kai Li
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Article
| Open Access
A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils
Rheumatoid arthritis (RA) involves several types of autoantibodies, which are usually considered pathogenic. In this study, the authors use phage display to develop antibodies targeting type-II collagen that are protective in multiple experimental models of RA.
- Zhongwei Xu
- , Bingze Xu
- & Rikard Holmdahl
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Article
| Open Access
Association of gout with brain reserve and vulnerability to neurodegenerative disease
The potential association between neurodegenerative disease risk and gout is not fully understood. Here the authors showed that gout is causally related to several measures of brain structure which may explain their higher vulnerability to dementia.
- Anya Topiwala
- , Kulveer Mankia
- & Thomas E. Nichols
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Article
| Open Access
Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis
Osteoarthritis is characterized by mechanically driven pain but lacks adequate treatments. Here, the authors show that inhibiting a mechanically-sensitive ion channel expressed by nociceptors reduces pain behaviors in mouse models of joint pain.
- Alia M. Obeidat
- , Matthew J. Wood
- & Rachel E. Miller
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Article
| Open Access
A machine learning model identifies patients in need of autoimmune disease testing using electronic health records
Early diagnosis can significantly improve treatment options and prevent severe organ damage in individuals with autoimmune diseases. Here, the authors develop a machine learning model that uses electronic health records to identify patients with clinical suspicion of autoimmune diseases.
- Iain S. Forrest
- , Ben O. Petrazzini
- & Ron Do
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Article
| Open Access
KIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration
The levels of a factor secreted by bone marrow stromal cells, KIAA1199, associate with osteoporotic fracture risk. Here, the authors show that KIAA1199 deficiency can lead to enhanced bone formation, accelerated bone healing, and protects from ovariectomy-induced bone loss.
- Li Chen
- , Kaikai Shi
- & Moustapha Kassem
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Article
| Open Access
Tryptase β regulation of joint lubrication and inflammation via proteoglycan-4 in osteoarthritis
Altered expression and function of the extracellular matrix protein PRG4 have been associated with osteoarthritis. Here, the authors show that mast cell tryptase β cleaves PRG4, resulting in a reduction of lubrication and activation of inflammation in this context.
- Nabangshu Das
- , Luiz G. N. de Almeida
- & Antoine Dufour
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Article
| Open Access
Affinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus
Antibodies directed against DNA in systemic lupus erythematosus are functionally diverse. This study demonstrates that DNAse1L3 is the primary target of a subset of autoantibodies previously considered specific for double-stranded DNA.
- Eduardo Gomez-Bañuelos
- , Yikai Yu
- & Felipe Andrade
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Article
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Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect
Allogeneic iPSC-derived cartilage organoids survive and integrate with surrounding native cartilage without immune reactions in a primate model of chondral defects in the knee joints, being remodeled and functioning as articular cartilage.
- Kengo Abe
- , Akihiro Yamashita
- & Noriyuki Tsumaki
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Article
| Open Access
A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis
Although anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis and generally considered pathogenic, their functional relevance is incompletely understood. In this study, the authors describe an ACPA with a protective effect against antibody-induced arthritis in mice.
- Yibo He
- , Changrong Ge
- & Rikard Holmdahl
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Article
| Open Access
Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis
The immune mechanisms underlying synovitis and joint tissue destruction in rheumatoid arthritis (RA) remain incompletely defined. Here, the authors demonstrate that ACPA+ RA patients have activated clonally expanded cytotoxic GZMB+ CD8+ T cells in blood and synovium that target and are activated by citrullinated antigens to mediate cell killing.
- Jae-Seung Moon
- , Shady Younis
- & William H. Robinson
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Article
| Open Access
Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity
Matrix stiffening is a quintessential feature of aged tissues. Authors show that an aged (stiff) matrix epigenetically represses the gene encoding the longevity factor, α-Klotho, resulting in chondrocyte dysfunction, a leading cause of osteoarthritis.
- Hirotaka Iijima
- , Gabrielle Gilmer
- & Fabrisia Ambrosio
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Article
| Open Access
Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
Some forms of mitochondrial dysfunction can cause sterile inflammation, but the way in which it might affect muscle fitness is not well understood. Here, the authors show that altered mitochondrial dynamics can cause the production of mitochondrial DNA-driven inflammatory signals mediated by endosome-mitochondria contacts, leading to muscle inflammation, atrophy, reduced physical performance and enhanced exercise-induced inflammatory responses.
- Andrea Irazoki
- , Isabel Gordaliza-Alaguero
- & Antonio Zorzano
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Article
| Open Access
Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open Access
Sirt6 attenuates chondrocyte senescence and osteoarthritis progression
Ji and colleagues identify Sirt6 as a regulator of chondrocyte senescence. Mechanistically, Sirt6 physically interacts with STAT5 and deacetylates it at K163, which reduces the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus.
- Ming-liang Ji
- , Hua Jiang
- & Jun Lu
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Article
| Open Access
Single-cell sequencing shows cellular heterogeneity of cutaneous lesions in lupus erythematosus
Discoid lupus erythematosus (DLE) and systemic LE (SLE) can present as cutaneous lesions. Here the authors characterise an scRNA dataset of cutaneous lesions from these patients and compare these to healthy controls showing differential immune cell recruitment, cell type and gene expression.
- Meiling Zheng
- , Zhi Hu
- & Ming Zhao
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Article
| Open Access
Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis
Fibrosis of the skin plays an important role in scleroderma. Here the authors demonstrate genetic and epigenetic abnormalities at the centromere that affect the replication of the chromosomes, resulting in activation of pathways involved in inflammation and fibrosis
- Souren Paul
- , Mark H. Kaplan
- & Rafael Contreras-Galindo
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Article
| Open Access
Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis
Hyperferritinemic syndrome is a collective term for a group of severe inflammatory conditions distinguished by high ferritin levels, including adult-onset Still’s disease and COVID-19. Here authors show in an animal model that high ferritin levels are not just a sign of hyperinflammation but also a pathogenic factor that triggers neutrophil leukocyte activation and extracellular trap formation.
- Jinchao Jia
- , Mengyan Wang
- & Qiongyi Hu
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Article
| Open Access
Osteocytes directly regulate osteolysis via MYD88 signaling in bacterial bone infection
MYD88 mediates the signal of bacterial infection. Here, in the context of periodontal infection, the authors show that the MYD88 pathway in osteocytes plays a dominant role in regulating osteolysis.
- Tetsuya Yoshimoto
- , Mizuho Kittaka
- & Yasuyoshi Ueki
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Article
| Open Access
Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs
A20 gene variants are linked with systemic sclerosis (SS), but the mechanisms are unclear. Here, the authors show that A20 expression is reduced in SS skin and lungs, that its ablation in mice induces SS, and that show that fibrosis can be ameliorated by induction of A20.
- Wenxia Wang
- , Swarna Bale
- & John Varga
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Article
| Open Access
Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development
Possible distinct contributions of Runx 2 and Runx3 in osteoarthritis have not been clarified. Nagata et al. show that Runx3 protects adult articular cartilage by extracellular matrix protein production in normal conditions, while Runx2 exerts both catabolic and anabolic effects during inflammation.
- Kosei Nagata
- , Hironori Hojo
- & Taku Saito
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Article
| Open Access
Immunogenicity decay and case incidence six months post Sinovac-CoronaVac vaccine in autoimmune rheumatic diseases patients
Characterising the response to SARS-CoV-2 post vaccination is critical in the appraisement of the induced immune response, performance and protective potential. Here the authors present data from a phase 4 clinical trial in autoimmune rheumatic disease patients 6 months post second dose of Sinovac-CoronaVac inactivated vaccine that show a marked reduction in antibody particularly in males or those under treatment with immune targeting therapies but saw no rise in COVID-19 disease.
- Clovis A. Silva
- , Ana C. Medeiros-Ribeiro
- & Eloisa Bonfa
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Article
| Open Access
Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells
The genetic architecture underlying Sjögren’s syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.
- Bhuwan Khatri
- , Kandice L. Tessneer
- & Christopher J. Lessard
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Article
| Open Access
Inhibitory role of Annexin A1 in pathological bone resorption and therapeutic implications in periprosthetic osteolysis
Periprosthetic osteolysis is a cause of arthroplasty failure without available therapies. Here the authors show that Annexin A1 (AnxA1) is involved in in periprosthetic osteolysis and exerts potential therapeutic effects through suppressing NFκB signaling and promoting the PPAR-γ pathway resulting in inhibition of inflammation and osteoclasts differentiation induced by wear debris.
- Hend Alhasan
- , Mohamad Alaa Terkawi
- & Norimasa Iwasaki
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Article
| Open Access
TGFβ reprograms TNF stimulation of macrophages towards a non-canonical pathway driving inflammatory osteoclastogenesis
Mechanisms for inflammatory osteolysis are unclear. Here, Xia et al. find that TGFβ shifts the inflammatory action of TNF on macrophages to a potent osteoclastogenic function and identify a novel TGFβ/TNF-mediated non-canonical osteoclastogenic program.
- Yuhan Xia
- , Kazuki Inoue
- & Baohong Zhao
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Poster
| Open Access
Immune monitoring and treatment in immune-mediated inflammatory diseases
Immune monitoring assists in the diagnosis and clinical management of immune-mediated inflammatory diseases.
- Femke van Wijk
- , Marjolein de Bruin
- & Stefan Nierkens
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Article
| Open Access
Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis
Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.
- William Damsky
- , Alice Wang
- & Brett King
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Article
| Open Access
Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis
Osteoarthritic (OA) is characterized by progressive destruction of joint cartilage. Here, the authors show that microRNA-17 plays a dual role in maintaining cartilage homeostasis and in the prevention of osteoarthritis, by targeting hypoxia-inducible factor-1α as well as multiple matrix-degrading enzymes.
- Yun Zhang
- , Shuaijun Li
- & Lei Cui
Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints