RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Isaacs, John D.; Brockbank, Sarah; Pedersen, Ayako Wakatsuki; Hilkens, Catharien; Anderson, Amy E.; Stocks, Philip; Lendrem, Dennis; Tarn, Jessica; Smith, Graham R.; Allen, Ben; Casement, John; Diboll, Julie; Harry, Rachel A.; Cooles, Faye A H; Cope, Andrew; Simpson, Gemma; Toward, Ruth; Noble, Hayley; Parke, A; Wu, Wen‐Jin; Clarke, F. H.; Scott, David J.; Scott, Ian C.; Galloway, James; Lempp, Heidi; Ibrahim, Fowzia; Schwank, Samana; Molyneux, Gemma; Lazarov, Tomi; Geissmann, Frédéric; Goodyear, Carl S.; McInnes, Iain B.; Donnelly, Iona; Gilmour, Ashley; Virlan, Aysın Tulunay; Porter, Duncan; Ponchel, Frédérique; Emery, Paul; El-Jawhari, Jehan J.; Parmar, Rekha; McDermott, Michael F.; Fisher, Benjamin A; Young, Steve; Jones, Philip H.; Raza, Karim; Filer, Andrew; Pitzalis, Costantino; Barnes, Michael R.; Watson, David S.; Henkin, Rafael; Thorborn, Georgina; Fossati-Jimack, Liliane; Kelly, Stephen; Humby, Frances; Bombardieri, Michèle; Rana, Sharmila; Jia, Zhilong; Goldmann, Katriona; Lewis, Myles; Ng, Sandra; Barbosa-Silva, Adriano; Tzanis, Evan; Gallagher-Syed, Amaya; John, Christopher R.; Ehrenstein, Michael R.; Altobelli, Giovanna Giuseppina; Martins, Sandra; Nguyen, Dao M.; Ali, Humayara; Ciurtin, Coziana; Buch, Maya H; Symmons, Deborah; Worthington, Jane; Bruce, Ian N; Sergeant, Jamie C.; Verstappen, Suzanne; Stirling, Fiona; Hughes-Morley, Adwoa; Tom, Brian D. M.; Farewell, Vernon; Zhong, Yujie; Taylor, Peter; Buckley, Christopher D.; Keidel, Sarah; Cuff, Carolyn A.; Levesque, Marc C.; Long, Andrew J.; Liu, Zheng; Lipsky, Samantha; Harvey, Bohdan P.; Macoritto, Michael; Hong, Feng; Kaymakçalan, S; Tsuji, Wayne; Sabin, Tony; Ward, Neil; Talbot, S.; Padhji, Desmond; Sleeman, Matthew A.; Finch, Donna K.; Herath, Athula; Lindholm, Catharina; Jenkins, Martin; Ho, Meilien; Hollis, Sally; Marshall, Chris; Parker, Adwoa; Page, Matt; Edwards, Hannah; Cuza, Alexandru Ioan; Gozzard, Neil; Pandis, Ioannis; Rowe, Anthony; Capdevila, Francisco Bonachela; Loza, Matthew; Curran, Mark; Verbeeck, Denny; Baker, D.; Mela, Christopher; Vranić, Ivana; Mela, Catherine T.; Wright, Stephen W.; Rowell, Lucy; Vernon, Emma; Joseph, Nina; Payne, Neil F.; Rao, Ravi; Binks, Michael; Belson, Alexandra; Ludbrook, Valerie J.; Hicks, Kirsty; Tipney, Hannah; Ellis, Joanne; Hasan, Samiul; Didierlaurent, Arnaud M.; Burny, Wivine; Haynes, Andrea; Larminie, Chris; Harris, R. I.; Dastros-Pitei, Daniela; Carini, Claudio; Kola, Blerina; Jelinsky, Scott A.; Hodge, Martin R.; Maciejewski, Mateusz; Ziemek, Daniel; Schulz‐Knappe, Peter; Zucht, Hans‐Dieter; Budde, Petra; Coles, Mark; Butler, James A.; Read, Simon

doi:10.1038/s41597-022-01264-y

Cited by 7 publications

(6 citation statements)

References 38 publications

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“…DMARD and glucocorticoid naive patients with eRA were recruited from the Newcastle Early Arthritis Clinic (NEAC) as described previously 6 8. Data and samples relating to the ‘Towards A CurE for RA’ (TACERA) cohort,9 an existing additional independent cohort of eRA was obtained from RA-MAP, a multicentre UK industry-academic partnership. All patients with eRA met the 198710 or 201011 RA classification criteria.…”

Section: Methodsmentioning

confidence: 99%

“…For TACERA at 6 months, DAS-28 was repeated, drug history recorded and additional biological samples were collected. All patients gave informed consent as described in Clark et al and RA-MAP Consortium 8 9…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral blood mononuclear cells (PBMCs) were isolated using Leucosep separation tubes (Greiner) followed by MagMAX RNA isolation kits (Ambion). For subsequent microarray analysis, amplified RNA was hybridised to beadchips and scanned on an Illumina Beadstation 500 as described further in 9. Full data are available via Gene Expression Omnibus database (GEO), http://www.ncbi.nlm.nih.gov/geo accession number GSE9747638.…”

Section: Methodsmentioning

confidence: 99%

“…For subsequent microarray analysis, amplified RNA was hybridised to beadchips and scanned on an Illumina Beadstation 500 as described further in. 9 Full data are available via Gene Expression Omnibus database (GEO), http://www.ncbi.nlm.nih.gov/geo accession number GSE9747638. Existing paired microarray gene expression and DNA methylation data from CD4+ T cells and CD19+ B cells extracted from NEAC eRA patients was preprocessed as described in Clark et al , 8 GEO accession number GSE137634.…”

Section: Methodsmentioning

confidence: 99%

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Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

et al. 2022

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ObjectivesAn interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.MethodsIn a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes.ResultsWe reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α).ConclusionsOur data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

et al. 2022

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“…Information on GSE97475 was obtained from the gene expression omnibus (ncbi.nlm.nih.gov/geo/) and accessed via the R package GEOquery June 10. 2023 36 . Finally, to analyze FOXP3 expression in KTRs, we used blood samples collected from KTRs enrolled in MoMoTx.…”

Section: Methodsmentioning

confidence: 99%

FOXP3 splice variant expression in males and females in healthy populations and in kidney transplant recipients

Saleh,

Mohammadnejad,

Tepel

2024

Sci Rep

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The forkhead box P3 (FOXP3) transcript is essential for tolerance of alloantigens. Here, we describe the expression of FOXP3 mRNA variants in healthy females and males, and in kidney transplant recipients (KTR). We measured FOXP3 in peripheral blood mononuclear cells from healthy kidney donors (N = 101), and in blood from KTRs (N = 248) before and after transplantation. FOXP3 was measured with quantitative polymerase chain reaction, and differentiated between pre-mature mRNA FOXP3, Total mature FOXP3, FOXP3 in which exon two is spliced, and full length FOXP3. We found similar levels of FOXP3 in healthy female and male kidney donors. We confirmed this result in a publicly available cohort (N = 33) of healthy individuals (GSE97475). Homogenously, female and male KTR FOXP3 levels were similar pre-transplantation, one day post-transplantation and 29 days post-transplantation. This may suggest that kidney transplantation and related immunosuppressive treatments do not influence FOXP3 expression differently in females and males. Finally, fold difference analysis revealed that KTRs express lower levels of mature FOXP3 and higher levels of pre-mature FOXP3 mRNA pre-transplant compared to healthy individuals. This finding may suggest higher pre-mRNA synthesis, lower pre-mRNA degradation, lower spliceosome efficiency or higher degradation of mature FOXP3 mRNA in kidney transplant candidates.

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Reduction of Proinflammatory Effector Functions Through Remodeling of Fatty Acid Metabolism in CD8+ T Cells From Rheumatoid Arthritis Patients

Kraus

Keck

Klika

et al. 2023

Arthritis & Rheumatology

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Objective. Rheumatoid arthritis (RA) CD8+ T cells maintain their effector proinflammatory phenotype by changing their metabolism toward aerobic glycolysis. However, their massive energy and biosynthesis needs may require additional substrates other than glucose. Since systemic alterations in lipid metabolism have been reported in RA patients, we explored the role of fatty acid (FA) metabolism in CD8+ T cells to identify potential targets to curb their proinflammatory potential.Methods. The expression of FA metabolism-related genes was analyzed for total CD8+ T cells and CD8+ T cell subsets in the data of RA patients and healthy controls retrieved from the GEO database. Functional assays were performed using peripheral blood CD8+ T cells isolated from RA (n = 31), psoriatic arthritis (n = 26), and spondyloarthritis (n = 21) patients receiving different therapies (disease-modifying antirheumatic drugs, biologics, and JAK inhibitors) and from healthy controls (n = 14). We quantified the expression of FA transporters, lipid uptake, intracellular FA content, cytokine production, activation, proliferation, and capacity to inhibit tumor cell growth, either with or without FA metabolism inhibitors.Results. The CD8+ T cell gene expression profile of FA metabolism-related genes was significantly different between untreated RA patients and healthy controls. RA patients who had a good clinical response after 6 months of methotrexate therapy had significantly increased expression of FA metabolism-related genes. Cell surface expression of the FA transporters FA binding protein 4 (FABP4) and G protein-coupled receptor 84 (GPR84) and FA uptake were higher in effector and memory CD8+ T cells from RA patients compared to those from healthy controls. In vitro blockade of FA metabolism significantly impaired CD8+ T cell effector functions.Conclusion. RA CD8+ T cells present an altered FA metabolism, which could provide potential therapeutic targets to control their proinflammatory profile, particularly therapies directed against the transport and oxidation of free FA.

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RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Cited by 7 publications

References 38 publications

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

FOXP3 splice variant expression in males and females in healthy populations and in kidney transplant recipients

Reduction of Proinflammatory Effector Functions Through Remodeling of Fatty Acid Metabolism in CD8+ T Cells From Rheumatoid Arthritis Patients

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