Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity.

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Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity.

Davis JM 3rd, Knutson KL, Strausbauch MA, Green AB, Crowson CS, Therneau TM, Matteson EL, Gabriel SE.

Journal		Arthritis Res Ther.
Species
Analytes Measured		G-CSF , GM-CSF , IL-10 , IL-12 Total , IL-13 , IL-17A , IL-2 , IL-4 , IL-5 , IL-6 , IL-7 , IL-8 , MCP-1
Matrix Tested		Cell culture supernatants

Year		2013
Volume		15
Page Numbers		199
Application		Cytokines and Chemokines

Abstract

INTRODUCTION: It remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA.

METHODS: A cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2.

RESULTS: A profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to CMV exposure.

CONCLUSIONS: A profile of T-cell immunity associated with CMV exposure influences the clinical response to DMARD therapy in patients with early RA. Because CMV latency is associated with greater joint destruction, our findings suggest that changes in T-cell immunity mediated by viral persistence may affect treatment response and possibly long-term outcomes of RA.

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V-PLEX Mouse IL-2 Kit IL-2 \| Mouse Singleplex		NEW
V-PLEX Proinflammatory Panel 1 Mouse Kit IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, KC/GRO, TNF-α \| Mouse Multiplex		NEW
V-PLEX Plus Chemokine Panel 1 (NHP) Gen. B Kit Eotaxin, Eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC \| Non-human primate Multiplex		NEW
V-PLEX Plus NHP MCP-1 Gen. B Kit MCP-1 \| Non-human primate Singleplex		NEW
V-PLEX NHP MCP-1 Gen. B Kit MCP-1 \| Non-human primate Singleplex		NEW
V-PLEX Chemokine Panel 1 (NHP) Gen. B Kit Eotaxin, Eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC \| Non-human primate Multiplex		NEW
V-PLEX Plus Chemokine Panel 1 (human) Gen. B Kit Eotaxin, Eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC \| Human Multiplex		NEW
V-PLEX Plus Human IL-2 Kit IL-2 \| Human Singleplex		NEW
V-PLEX Human IL-2 Kit IL-2 \| Human Singleplex		NEW
V-PLEX Plus Human IL-8 Kit IL-8 \| Human Singleplex		NEW
V-PLEX Human IL-8 Kit IL-8 \| Human Singleplex		NEW
V-PLEX Human IL-17A Kit IL-17A \| Human Singleplex		NEW
V-PLEX Human IL-5 Kit IL-5 \| Human Singleplex		NEW
V-PLEX Plus Human IL-5 Kit IL-5 \| Human Singleplex		NEW
V-PLEX NHP GM-CSF Kit GM-CSF \| Non-human primate Singleplex		NEW
V-PLEX NHP IL-17A Kit IL-17A \| Non-human primate Singleplex		NEW
V-PLEX NHP IL-5 Kit IL-5 \| Non-human primate Singleplex		NEW
V-PLEX Plus NHP GM-CSF Kit GM-CSF \| Non-human primate Singleplex		NEW
V-PLEX Plus NHP IL-17A Kit IL-17A \| Non-human primate Singleplex		NEW
V-PLEX Plus NHP IL-5 Kit IL-5 \| Non-human primate Singleplex		NEW
V-PLEX Plus Human IL-17A Kit IL-17A \| Human Singleplex		NEW
V-PLEX Plus NHP IL-2 Kit IL-2 \| Non-human primate Singleplex		NEW
V-PLEX NHP IL-8 Kit IL-8 \| Non-human primate Singleplex		NEW
V-PLEX NHP IL-2 Kit IL-2 \| Non-human primate Singleplex		NEW
V-PLEX Plus NHP IL-8 Kit IL-8 \| Non-human primate Singleplex		NEW
V-PLEX Plus NHP IL-7 Kit IL-7 \| Non-human primate Singleplex		NEW
V-PLEX Plus NHP IL-6 Kit IL-6 \| Non-human primate Singleplex		NEW
V-PLEX Plus Human IL-7 Kit IL-7 \| Human Singleplex		NEW
V-PLEX Plus Human IL-6 Kit IL-6 \| Human Singleplex		NEW
V-PLEX Plus Cytokine Panel 1 NHP Kit GM-CSF, IL-5, IL-7, IL-12/IL-23p40, IL-15, IL-16, IL-17A, TNF-β, VEGF-A \| Non-human primate Multiplex		NEW
V-PLEX Plus Cytokine Panel 1 Human Kit GM-CSF, IL-1α, IL-5, IL-7, IL-12/IL-23p40, IL-15, IL-16, IL-17A, TNF-β, VEGF-A \| Human Multiplex		NEW
V-PLEX NHP IL-7 Kit IL-7 \| Non-human primate Singleplex		NEW
V-PLEX Human IL-7 Kit IL-7 \| Human Singleplex		NEW
V-PLEX Human IL-6 Kit IL-6 \| Human Singleplex		NEW
V-PLEX Plus Human MCP-1 Gen. B Kit MCP-1 \| Human Singleplex		NEW
V-PLEX Human MCP-1 Gen. B Kit MCP-1 \| Human Singleplex		NEW
V-PLEX NHP IL-6 Kit IL-6 \| Non-human primate Singleplex		NEW
V-PLEX Plus NHP IL-10 Kit IL-10 \| Non-human primate Singleplex		NEW
V-PLEX Plus Human IL-10 Kit IL-10 \| Human Singleplex		NEW
V-PLEX NHP IL-10 Kit IL-10 \| Non-human primate Singleplex		NEW
V-PLEX Human IL-10 Kit IL-10 \| Human Singleplex		NEW
V-PLEX Chemokine Panel 1 (human) Gen. B Kit Eotaxin, Eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC \| Human Multiplex		NEW
V-PLEX Plus Human GM-CSF Kit GM-CSF \| Human Singleplex		NEW
V-PLEX Human GM-CSF Kit GM-CSF \| Human Singleplex		NEW
V-PLEX Cytokine Panel 1 NHP Kit GM-CSF, IL-5, IL-7, IL-12/IL-23p40, IL-15, IL-16, IL-17A, TNF-β, VEGF-A \| Non-human primate Multiplex		NEW
V-PLEX Cytokine Panel 1 Human Kit GM-CSF, IL-1α, IL-5, IL-7, IL-12/IL-23p40, IL-15, IL-16, IL-17A, TNF-β, VEGF-A \| Human Multiplex		NEW
V-PLEX Proinflammatory Panel 1 Human Kit IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α \| Human Multiplex		NEW
V-PLEX Proinflammatory Panel 1 NHP Kit IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10 \| Non-human primate Multiplex		NEW
V-PLEX Viral Panel 2 NHP Kit IFN-γ, IL-1β, IL-6, IL-8, IL-10 \| Non-human primate Multiplex		NEW
V-PLEX Viral Panel 2 Human Kit IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-10, TNF-α \| Human Multiplex		NEW
V-PLEX Viral Panel 1 NHP Kit IL-1β, IL-6, IL-8 \| Non-human primate Multiplex		NEW
V-PLEX Viral Panel 1 Human Kit IL-1β, IL-6, IL-8, TNF-α \| Human Multiplex		NEW
V-PLEX Plus Proinflammatory Panel 1 Human Kit IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α \| Human Multiplex		NEW
V-PLEX Plus Proinflammatory Panel 1 NHP Kit IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10 \| Non-human primate Multiplex		NEW
V-PLEX Plus Human Proinflam. Panel II (4-Plex) IL-1β, IL-6, IL-8, TNF-α \| Human Multiplex		NEW
V-PLEX Plus Human Proinflam. Panel I (4-Plex) IFN-γ, IL-1β, IL-6, TNF-α \| Human Multiplex		NEW
V-PLEX Plus Human IL-13 Kit IL-13 \| Human Singleplex		NEW
V-PLEX Plus Human IL-4 Kit IL-4 \| Human Singleplex		NEW
V-PLEX Human Proinflammatory Panel II (4-Plex) IL-1β, IL-6, IL-8, TNF-α \| Human Multiplex		NEW
V-PLEX Human Proinflammatory Panel I (4-Plex) IFN-γ, IL-1β, IL-6, TNF-α \| Human Multiplex		NEW
V-PLEX Human IL-13 Kit IL-13 \| Human Singleplex		NEW
V-PLEX Human IL-4 Kit IL-4 \| Human Singleplex		NEW
V-PLEX Plus Viral Panel 2 NHP Kit IFN-γ, IL-1β, IL-6, IL-8, IL-10 \| Non-human primate Multiplex		NEW
V-PLEX Plus Viral Panel 2 Human Kit IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-10, TNF-α \| Human Multiplex		NEW
V-PLEX Plus Viral Panel 1 NHP Kit IL-1β, IL-6, IL-8 \| Non-human primate Multiplex		NEW
V-PLEX Plus Viral Panel 1 Human Kit IL-1β, IL-6, IL-8, TNF-α \| Human Multiplex		NEW
R-PLEX Rabbit IL-6 Antibody Set IL-6 \| Rabbit		NEW
R-PLEX Rabbit IL-6 Assay IL-6 \| Rabbit Singleplex		NEW
U-PLEX Biomarker Group 1 (NHP) Assays CTACK, ENA-78, Eotaxin, Eotaxin-2, Eotaxin-3, FLT3L, Fractalkine, G-CSF, GM-CSF, GRO-α, I-309, IFN-α2a, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17B, IL-17C, IL-17D, IL-17F, IL-18, IL-22, IL-23, IP-10, I-TAC, MCP-1, MCP-2, MCP-4, M-CSF, MDC, MIF, MIP-1α, MIP-1β, MIP-3α, MIP-3β, MIP-5, SDF-1α, TARC, TNF-α, TNF-β, TPO, TRAIL, VEGF-A, YKL-40 \| Non-human primate Multiplex
U-PLEX Custom Biomarker Group 1 (human) Assays CTACK, ENA-78, Eotaxin, Eotaxin-2, Eotaxin-3, EPO, FLT3L, Fractalkine, G-CSF, GM-CSF, GRO-α, I-309, IFN-α2a, IFN-β, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-2Rα, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-27, IL-29/IFN-λ1, IL-31, IL-33, IP-10, I-TAC, MCP-1, MCP-2, MCP-3, MCP-4, M-CSF, MDC, MIF, MIP-1α, MIP-1β, MIP-3α, MIP-3β, MIP-5, SDF-1α, TARC, TNF-α, TNF-β, TPO, TRAIL, TSLP, VEGF-A, YKL-40 \| Human Multiplex
U-PLEX Custom Biomarker Group 1 (mouse) Assays 6CKine/CCL21, BAFF, BCA-1/BLC, CD40/TNFRSF5, Eotaxin, EPO, GM-CSF, IFN-α, IFN-β, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17C, IL-17E/IL-25, IL-17F, IL-21, IL-22, IL-23, IL-27p28/IL-30, IL-31, IL-33, IP-10, KC/GRO, MCP-1, MCP-5/CCL12, MDC, MIP-1α, MIP-1β, MIP-2, MIP-3α, MMP-9 (total), NGAL/LCN2, RANTES, SDF-1α, TARC, TNF-α, TNF-RI, VEGF-A \| Mouse Multiplex
U-PLEX Custom Metabolic Group 1 (human) Assays BAFF, BDNF, β-NGF, C-Peptide, CTACK, ENA-78, Eotaxin, Eotaxin-2, Eotaxin-3, EPO, FGF-21, FGF-23, FLT3L, Fractalkine, FSH, G-CSF, Ghrelin (active), Ghrelin (total), GIP (active), GIP (inactive), GIP (total), GLP-1 (active), GLP-1 (inactive), GLP-1 (total), Glucagon, GM-CSF, GRO-α, I-309, IFN-α2a, IFN-β, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-2Rα, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17C, IL-17D, IL-17E/IL-25, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-27, IL-29/IFN-λ1, IL-31, IL-33, Insulin, IP-10, Leptin, Luteinizing Hormone (LH), MCP-1, MCP-2, MCP-4, M-CSF, MDC, MIF, MIP-1α, MIP-5, PP, Proinsulin, PYY (total), SDF-1α, TARC, TNF-α, TNF-β, TPO, TRAIL, TSLP, VEGF-A, YKL-40 \| Human Multiplex
U-PLEX Custom Metabolic Group 1 (mouse) Assays BAFF, BCA-1/BLC, BDNF, CD40/TNFRSF5, C-Peptide, Eotaxin, EPO, FGF-21, Ghrelin (active), Ghrelin (total), GLP-1 (active), GLP-1 (inactive), GLP-1 (total), Glucagon, GM-CSF, IFN-α, IFN-β, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17C, IL-17E/IL-25, IL-17F, IL-21, IL-22, IL-23, IL-27p28/IL-30, IL-31, IL-33, Insulin, IP-10, KC/GRO, Leptin, MCP-1, MCP-5/CCL12, MDC, MIP-1α, MIP-1β, MIP-2, MIP-3α, MMP-9 (total), PYY (total), RANTES, TARC, TNF-α, VEGF-A \| Mouse Multiplex
U-PLEX Custom Immuno-Oncology Group 1 (human) Assays 4-1BBL/TNFSF9, APRIL/TNFSF13, BAFF-R/TNFRSF13C, BCMA/TNFRSF17, BTLA, CD20, CD27, CD28, CD40/TNFRSF5, CD40L (soluble), CD80/B7-1, CD276/B7-H3, CTACK, CTLA-4, E-Cadherin, ENA-78, Eotaxin, Eotaxin-2, Eotaxin-3, EPO, E-Selectin, Fas (soluble), FasL, FGF (basic), FLT3L, Fractalkine, Galectin-9, G-CSF, GITR/TNFRSF18, GITRL/TNFSF18, GM-CSF, gp130 (soluble), Granzyme A, Granzyme B, GRO-α, HAVCR1/KIM-1, HAVCR2/TIM-3, HVEM/TNFRSF14, I-309, ICOS, ICOS-L/B7-H2, IDO-1, IFN-α2a, IFN-β, IFN-γ, IL-1α, IL-1β, IL-1RA, IL-2, IL-2Rα, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, IL-17A/F, IL-17C, IL-17D, IL-17E/IL-25, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-27, IL-29/IFN-λ1, IL-31, IL-33, IP-10, I-TAC, LAG3, LIGHT/TNFSF14, MCP-1, MCP-2, MCP-4, M-CSF, MDC, MIF, MIG, MIP-1α, MIP-1β, MIP-5, MMP-1, MMP-2, MMP-7, MMP-8 (total), MMP-9 (total), MMP-10 (total), Nectin-4, OX40/TNFRSF4, PD1 (epitope 1), PD1 (epitope 2), PDGF-B, PD-L1 (epitope 1), PD-L1 (epitope 2), PD-L2, Pentraxin 3, Perforin, PlGF, proMMP-8, proMMP-9, proMMP-10, P-Selectin, RAGE (soluble), RANKL/TNFSF11, RANTES, S100A12, TACI/TNFRSF13B, Tie-2, TIGIT, TLR1, TNF-α, TNF-β, TNF-RI, TNF-RII, TPO, TRAIL, TSLP, VEGF-A, VEGF-D, VEGFR-1/Flt-1, YKL-40 \| Human Multiplex
U-PLEX Alzheimer's Disease Combo 1 (human) Eotaxin, IL-1α, IL-12/IL-23p40, IL-16, IL-17A, MCP-1, MDC, MIF, SDF-1α, YKL-40 \| Human Multiplex
U-PLEX Multiple Sclerosis Combo 1 (human) CTACK, Fractalkine, GRO-α, IL-7, IL-12/IL-23p40, IP-10, MCP-1, MIP-1β, MIP-3α \| Human Multiplex
U-PLEX TBI Combo 1 (human) CD40L (soluble), Fractalkine, IFN-γ, IL-1β, IL-6, IL-18, MCP-1, RANKL/TNFSF11, TNF-α, VEGF-D \| Human Multiplex
U-PLEX Chemokine Combo (mouse) IP-10, KC/GRO, MCP-1, MIP-1α, MIP-1β, MIP-2, MIP-3α \| Mouse Multiplex
U-PLEX Chemokine Combo 1 (human) Eotaxin, Eotaxin-2, Eotaxin-3, IL-8, IP-10, MCP-1, MCP-2, MCP-3, MCP-4, MDC, MIP-1α, MIP-1β, TARC \| Human Multiplex		NEW
U-PLEX Chemokine Combo 1 (mouse) IP-10, KC/GRO, MCP-1, MDC, MIP-1α, MIP-1β, MIP-2, MIP-3α \| Mouse Multiplex
U-PLEX Chemokine Combo 1 (NHP) Eotaxin, Eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1β, TARC \| Non-human primate Multiplex		NEW
U-PLEX Cytokine Combo 1 (human) GM-CSF, IL-1α, IL-5, IL-7, IL-12/IL-23p40, IL-15, IL-16, IL-17A, TNF-β, VEGF-A \| Human Multiplex		NEW
U-PLEX Cytokine Combo 1 (NHP) GM-CSF, IL-1α, IL-5, IL-7, IL-12/IL-23p40, IL-15, IL-16, IL-17A, TNF-β, VEGF-A \| Non-human primate Multiplex		NEW
U-PLEX Macrophage M1 Combo 1 (human) IL-1β, IL-6, IL-12p70, IL-18, IL-23, IP-10, MCP-1, MIP-1α, TNF-α \| Human Multiplex
U-PLEX Macrophage M1 Combo 1 (mouse) IL-1β, IL-6, IL-12p70, IL-15, IL-23, IP-10, MCP-1, MIP-1α, TNF-α \| Mouse Multiplex
U-PLEX Macrophage M2 Combo 1 (human) Eotaxin-2, IL-4, IL-10, IL-13, M-CSF, MDC, TARC \| Human Multiplex
U-PLEX Macrophage M2 Combo 1 (mouse) IL-4, IL-10, IL-13, MDC, TARC \| Mouse Multiplex
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Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity.

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