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Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

ABSTRACT: Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

SUBMITTER: Penkava F

PROVIDER: S-EPMC7505844 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

Penkava Frank F Velasco-Herrera Martin Del Castillo MDC Young Matthew D MD Yager Nicole N Nwosu Lilian N LN Pratt Arthur G AG Lara Alicia Lledo AL Guzzo Charlotte C Maroof Ash A Mamanova Lira L Cole Suzanne S Efremova Mirjana M Simone Davide D Filer Andrew A Brown Chrysothemis C CC Croxford Andrew L AL Isaacs John D JD Teichmann Sarah S Bowness Paul P Behjati Sam S Hussein Al-Mossawi M M

Nature communications 20200921 1

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show ...[more]

PMID: 32958743

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Project description:ObjectiveGenetic associations imply a role for CD8+ T cells and the interleukin-23 (IL-23)/IL-17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL-17A+CD8+ (Tc17) T cells are enriched in the synovial fluid (SF) of patients with PsA, and IL-17A blockade is clinically efficacious in PsA/SpA. This study was undertaken to determine the immunophenotype, molecular profile, and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis.MethodsPeripheral blood (PB) and SF mononuclear cells were isolated from patients with PsA or other types of SpA. Cells were phenotypically, transcriptionally, and functionally analyzed by flow cytometry (n = 6-18), T cell receptor β (TCRβ) sequencing (n = 3), RNA-Seq (n = 3), quantitative reverse transcriptase-polymerase chain reaction (n = 4), and Luminex or enzyme-linked immunosorbent assay (n = 4-16).ResultsIL-17A+CD8+ T cells were predominantly TCRαβ+ and their frequencies were increased in the SF versus the PB of patients with established PsA (P < 0.0001) or other SpA (P = 0.0009). TCRβ sequencing showed that these cells were polyclonal in PsA (median clonality 0.08), while RNA-Seq and deep immunophenotyping revealed that PsA synovial Tc17 cells had hallmarks of Th17 cells (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue-resident memory T (Trm) cell signature and secreted a range of proinflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 in PsA SF (P = 0.0005), which may contribute to their retention in the joint.ConclusionOur results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA.

Project description:IntroductionEicosanoids are biological lipids that serve as both activators and suppressors of inflammation. Eicosanoid pathways are implicated in synovitis and joint destruction in inflammatory arthritis, yet they might also have a protective function, underscoring the need for a comprehensive understanding of how eicosanoid pathways might be imbalanced. Until recently, sensitive and scalable methods for detecting and quantifying a high number of eicosanoids have not been available.ObjectiveHere, we intend to describe a detailed eicosanoid profiling in patients with psoriatic arthritis (PsA) and evaluate correlations with parameters of disease activity.MethodsForty-one patients with PsA, all of whom satisfied the CASPAR classification criteria for PsA, were studied. Outcomes reflecting the activity of peripheral arthritis as well as skin psoriasis, Disease Activity Score (DAS)28, Clinical Disease Index (CDAI) and Body Surface Area (BSA) were assessed. Serum eicosanoids were determined by LC-MS, and the correlation between metabolite levels and disease scores was evaluated.ResultsSixty-six eicosanoids were identified by reverse-phase LC/MS. Certain eicosanoids species including several pro-inflammatory eicosanoids such as PGE2, HXB3 or 6,15-dk,dh,PGF1a correlated with joint disease score. Several eicosapentaenoic acid (EPA)-derived eicosanoids, which associate with anti-inflammatory properties, such as 11-HEPE, 12-HEPE and 15-HEPE, correlated with DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) as well. Of interest, resolvin D1, a DHA-derived anti-inflammatory eicosanoid, was down-regulated in patients with high disease activity.ConclusionBoth pro- and anti-inflammatory eicosanoids were associated with joint disease score, potentially representing pathways of harm as well as benefit. Further studies are needed to determine whether these eicosanoid species might also play a role in the pathogenesis of joint inflammation in PsA.

Project description:The aim was to study changes in immunohistochemical expression markers of synovial and skin inflammation, clinical outcomes and magnetic resonance imaging (MRI) scores with abatacept treatment in patients with psoriatic arthritis (PsA).Biological-treatment-naïve PsA patients with active disease including synovitis of a knee were enrolled in this single-centre, crossover study. Patients were randomised to receive intravenous abatacept 3 mg/kg of body weight or placebo infusion on day 1, 15 and 29; thereafter abatacept 10 mg/kg of body weight was administered every 28 days for 5 months. Clinical data were collected at each visit. Synovial biopsy of the involved knee was obtained at baseline and 2 and 6 months. MRI of the same knee and skin biopsy was performed prior to arthroscopy.Fifteen patients were recruited. Significant improvements in the joint-related measures were observed; 90% were European League Against Rheumatism criteria responders and 30% achieved psoriasis area severity index (PASI)50 at 6 months. Reduction in synovitis (P?=?0.016) and vascularity (P?=?0.039) macroscopic scores consistent with decrease in total MRI score (P?=?0.016) were noticed. Abatacept decreased the immunohistological expression of FOXP3+ cells (P?=?0.027), specifically the expression of CD4+FOXP3+ regulatory T cells (Tregs) (P?=?0.008) in the synovium over 6 months. There was no significant clinical or immunohistological change in any of the skin measures.This is the first study assessing synovial and psoriatic skin immunpathological changes following abatacept treatment in PsA. Reduction in Treg expression in the synovium but not in the psoriatic lesion suggests abnormal Treg function in PsA with differential suppressive capacity in the synovium compared to the lesional skin. The results of this study demonstrate that abatacept 10 mg/kg of body weight might be an effective treatment option for joint disease in patients with PsA.Irish Health Products Regulatory Authority.CT 900/489/1 - Abatacept (case number: 2077284, EudraCT Number: 2009-017525-19, Protocol number: 77777). Registered on 12 March 2010.

Project description:BackgroundDifferential diagnosis among psoriatic arthritis (PsA) and seronegative rheumatoid arthritis (Abneg RA) can be challenging particularly in the clinical setting of peripheral phenotype and autoantibodies seronegativity. The aim of the study was to identify synovial tissue (ST) biomarkers differentially expressed in PsA and Abneg RA and test their predictive value of therapeutic response.MethodsThirty-four PsA patients [12 DMARD naive and 22 non-responder to methotrexate (MTX-IR)] with peripheral joint involvement and 55 Abneg RA (27 DMARD naive and 28 MTX-IR) underwent US-guided ST biopsy and immunohistochemistry (IHC) for CD68+, CD3+, CD20+, CD21+, CD117+, and CD138+ cells. After study entry, each DMARD-naive patient started MTX therapy and was followed in an outpatient setting for at least 6 months to define the achievement of Minimal Disease Activity (PsA) and DAS remission (Abneg RA) status respectively. Each IR-MTX patient was treated according to EULAR recommendations.ResultsAt study entry, IHC analysis revealed that PsA patients had comparable levels of lining and sublining CD68+ and sublining CD21+, CD20+, and CD3+ cells than Abneg RA, despite the therapeutic regimen. Moreover, regardless of the therapeutic scheme, PsA patients showed higher IHC score of CD117+ cells (p = 0.0004 and p = 0.0005 for naive and MTX-IR patients respectively) compared to Abneg RA patients. Conversely, Abneg RA patients showed higher IHC score of CD138+ cells, irrespective to the therapeutic scheme (p = 0.04 and p = 0.002 for naive and MTX-IR patients respectively). Analyzing the response rate to the therapeutic scheme, naive PsA patients reaching MDA status at 6 months follow-up, showed, at the study entry, lower IHC score of CD3+ cells compared to PsA patients not reaching this outcome (p = 0.02); conversely, naive Abneg RA patients reaching DAS remission status at 6 months follow-up, showed, at the study entry, lower IHC score of sublining CD68+ cells compared to Abneg RA patients not reaching this outcome (p < 0.001).ConclusionsCD117+ and CD138+ cells are differentially distributed among PsA and Abneg RA. Histological analysis of ST may help to solve the clinical overlap between the two diseases and provides prognostic data about the therapy success.

Project description:Many aged individuals develop monoclonal expansions of CD8 T cells. These expansions are derived from a CD8 memory T cell that outcompetes neighboring CD8 T cells. The molecular alterations within clonal expansions that confer this competitive advantage relative to other CD8 T cells remains unknown. These microarray experiments were designed to identify genes differentially expressed in age-associated expansions of CD8 memory T cells relative to polyclonal CD8 memory T cells found in the same aged mice. Subsequent analysis of these data identified two major types of clonal expansions, distinguished by expression level of integrin a4 mRNA and protein. Based on this classification, Expansion_rep1 belongs to the integrin a4 high subtype of clonal expansions. In contrast, reps 2, 4, and 5 belong to the integrin a4 low subtype of clonal expansions. Given the divergent biological properties of these two subtypes of clonal expansions, we have focused genes differentially expressed between Expansion_rep 2, 4, and 5 and their paired PolyclonalAged samples. Experiment Overall Design: A total of 8 samples were analyzed for gene expression using the Affymetrix mouse genome 430 2.0 microarray platform. The experimental samples of interest were age-associated clonal expansions of CD8 memory T cells. We purified four clonal expansions from four independent, aged mice (indicated as "Expansion" rep1 2, 3, 4). For each clonal expansion of CD8 memory T cells that was purified, there was a paired control in which polyclonal CD8 memory T cells were harvested from the same aged mouse (denoted as "PolyclonalAged" rep1, 2, 3, 4). These paired samples allow one to consider gene expression changes from mice which have undergone the same age-associated changes in biology. The predominant comparison this study focused on was changes in gene expression between age-associated clonal expansions of CD8 memory T cells and their paired, polyclonal CD8 memory T cells. A total of 4 of these pairs were collected.

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Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

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Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

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