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IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters.MethodsSynovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets.ResultsWe show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion.DiscussionIn this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.

Additional file 2: Characteristics of included publications

Additional file 1: COMET database search

Additional file 3: Outcome measures proposed across inflammatory conditions

Additional file of Rheumatoid synovial fluid interleukin-17-producing CD4 T cells have abundant tumor necrosis factor-alpha co-expression, but little interleukin-22 and interleukin-23R expression

Background Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci. Results We identify putative causal variants, enhancers, genes, and cell types for 30–60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Conclusion Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-021-02460-6.

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Additional file 4:. Dataset S2. Known motif enrichment analysis using HOMER at enhancer sites with open chromatin.

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Additional file 3:. Dataset S1. Quality control measures.

Additional file 9:. Review history

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Background It has been hypothesized that chronic inflammatory diseases such as rheumatoid arthritis (RA) may be caused by a failure of negative feedback mechanisms. This study sought to examine negative feedback mechanisms in fibroblast-like synoviocytes (FLS), one of the most abundant cell types in the joint. We hypothesized that prior exposure of healthy FLS to an inflammatory stimulus would attenuate their responses to a second inflammatory stimulus, in the same way that negative feedback mechanisms desensitize macrophages to repeated stimulation by lipopolysaccharide. We further hypothesized that such negative feedback mechanisms would be defective in FLS derived from the joints in RA. Methods Synovial fibroblasts and dermal fibroblasts from non-inflamed joints and joints affected by RA and a fibroblast cell line from neonatal foreskin were stimulated twice with tumour necrosis factor (TNF) α or interleukin (IL)-1α, with a 24-h rest period between the two 24-h stimulations. Differences between response to the first and second dose of cytokine were examined by assessing secretion of inflammatory factors and intracellular signalling activity. Results FLS from both non-inflamed joints and joints affected by RA mounted an augmented response to re-stimulation. This response was site-specific, as primary dermal fibroblasts did not alter their response between doses. The fibroblast priming was also gene-specific and transient. Assessment of signalling events and nuclear localization showed prolonged activation of nuclear factor (NF)-κB during the second stimulation. Conclusion This study aimed to examine mechanisms of negative regulation of inflammatory responses in FLS. Instead, we found a pro-inflammatory stromal memory in FLS obtained from both non-inflamed joints and joints affected by RA. This suggests the joint is an area at high risk of chronic inflammation, and may provide a piece in the puzzle of how chronic inflammation is established in RA. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1248-6) contains supplementary material, which is available to authorized users.

Sources of data for quantitative survey of loom technologies

S1: Background, methods and data supplement 1. A primer on looms and weaving 2. Archaeological remains of looms in East Asia 3. Cultural transmission of weaving traditions: a review of published sources 4. Materials and methods: additional notes 5. A model for the evolution of loom technology

The Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE) is a partnership between researchers at Newcastle University, the University of Birmingham and the University of Glasgow. Established in 2013, it is funded for 5 years, with a grant of £2.5 million from Arthritis Research UK and a further £4 million pledged by the three universities. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune condition that affects the joints and internal organs. Synovial inflammation can cause cartilage and bone damage with resultant joint destruction and associated disability. RACE aims to identify biological mechanisms involved in the initiation of RA and its progression to a chronic disease, and to identify novel therapeutic targets for control and cure. It has long been recognized that patients' experience complements researchers' skills (Hewlett et al., 2006). At the outset of the RACE project, it was agreed that patient engagement and involvement was crucial to facilitate the translation of research undertaken by the centre into public benefit. The present paper reports on a conference held at the University of Birmingham in January 2016 to bring together patient and public involvement (PPI) representatives from each hub, and to provide patients' and carers' perspectives on the following questions: What should research charities focus their spending on? How can people with RA influence the research agenda? What are the best ways for scientists to feed back to patients, relatives and carers about research findings?

Background: Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. Methodology/Principal Findings: We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. Conclusions: The gonochoristic species display a significantly longer lifespan (p