Distinct DNA Methylation Patterns of Rheumatoid Arthritis Peripheral Blood and Synovial Tissue T Cells

Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid arthritis and 18 healthy volunteers. We also used anti-CD3 and anti-CD3 + IL-2 stimulation as controls. The suppressive activity of Treg cells was evaluated in each case by the inhibition of the proliferation of CD4+ and CD8+ cells. The phenotype and proliferation of purified CD3+CD4+CD25+CD127lo cells were assessed by flow cytometry. The suppressive activity of the total pool of Tregs did not differ between the rheumatoid arthritis and healthy donors; however, it significantly decreased in conditions close to fast HP when the influence of HP cytokines was accompanied by anti-CD3 stimulation. The Treg proliferation caused by HP cytokines was lower in the rheumatoid arthritis (RA) patients than in the healthy individuals. The revealed decrease in Treg suppressive activity could impact the TCR landscape during lymphopenia and lead to the proliferation of potentially self-reactive T cell clones that are able to receive relatively strong TCR signals. This may be another explanation as to why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease in Treg proliferation under IL-7 and IL-15 exposure can lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis in the case of lymphopenia.

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Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate

Arthritis Research & Therapy ◽

10.1186/s13075-015-0748-5 ◽

2015 ◽

Vol 17 (1) ◽

Cited By ~ 61

Author(s):

María C. de Andres ◽

Eva Perez-Pampin ◽

Manuel Calaza ◽

Francisco J. Santaclara ◽

Ignacio Ortea ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Dna Methylation ◽

Blood Cell ◽

Early Rheumatoid Arthritis ◽

Peripheral Blood ◽

Peripheral Blood Cell ◽

Global Dna Methylation ◽

Before And After ◽

Cell Subpopulations

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Different T cells' distribution and activation degree of Th17 CD4+ cells in peripheral blood in patients with osteoarthritis, rheumatoid arthritis, and healthy donors: preliminary results of the MAGENTA CLICAO study

Open Access Rheumatology Research and Reviews ◽

10.2147/oarrr.s81905 ◽

2015 ◽

pp. 63 ◽

Cited By ~ 9

Author(s):

Alfredo Maria Lurati ◽

antonella laria ◽

Ariannna Gatti ◽

Bruno Brando ◽

magda scarpellini

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Peripheral Blood ◽

Cd4 Cells ◽

Preliminary Results ◽

Healthy Donors

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Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.738481 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maaria Palmroth ◽

Krista Kuuliala ◽

Ritva Peltomaa ◽

Anniina Virtanen ◽

Antti Kuuliala ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Treatment Response ◽

Peripheral Blood ◽

Janus Kinase ◽

Cytokine Signaling ◽

Stat3 Phosphorylation ◽

Stat Pathway

ObjectiveCurrent knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.MethodsSixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.ResultsTofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.ConclusionsTofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

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Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2005.037176 ◽

2006 ◽

Vol 65 (3) ◽

pp. 294-300 ◽

Cited By ~ 138

Author(s):

J J Haringman

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Tissue ◽

Peripheral Blood Mononuclear Cells ◽

Chemokine Receptor ◽

Peripheral Blood ◽

Reactive Arthritis ◽

Mononuclear Cells ◽

Receptor Expression ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

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Decreased MiR-128-3p alleviates the progression of rheumatoid arthritis by up-regulating the expression of TNFAIP3

Bioscience Reports ◽

10.1042/bsr20180540 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 11

Author(s):

Zhongbin Xia ◽

Fanru Meng ◽

Ying Liu ◽

Yuxuan Fang ◽

Xia Wu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Peripheral Blood ◽

Potential Role ◽

Enzyme Linked Immunosorbent Assay ◽

Normal Person ◽

Synovial Joint ◽

Peripheral Blood Mononuclear

Background: Rheumatoid arthritis (RA) is a inflammatory disease that characterized with the destruction of synovial joint, which could induce disability. Inflammatory response mediated the RA. It has been reported that MiR-128-3p is significantly increased in RA, while the potential role was still unclear. Methods: T cells in peripheral blood mononuclear cell (PBMC) were isolated from the peripheral blood from people of RA and normal person were used. Real-time PCR was performed to detect the expression of MiR-128-3p, while the protein expression of tumor necrosis factor-α-induced protein 3 (TNFAIP3) was determined using Western blot. The levels of IL-6 and IL-17 were measured using enzyme-linked immunosorbent assay (ELISA). The expression of CD69 and CD25 was detected using flow cytometry. The RA mouse model was constructed for verification of the role of MiR-128-3p. Results: The expression of MiR-128-3p was significantly increased, while TNFAIP3 was decreased, the levels of IL-6 and IL-17 were also increased in the T cells of RA patients. Down-regulated MiR-128-3p significantly suppressed the expression of p-IkBα and CD69, and CD25in T cells. MiR-128-3p targets TNFAIP3 to regulate its expression. MiR-128-3p knockdown significantly suppressed the activity of nuclear factor κB (NF-κB) and T cells by up-regulating TNFAIP3, while cells co-transfected with si-TNFAIP3 abolished the effects of MiR-128-3p knockdown. The in vivo experiments verified the potential role of MiR-128-3p on RA. Conclusion: Down-regulated MiR-128-3p significantly suppressed the inflammation response of RA through suppressing the activity of NF-κB pathway, which was mediated by TNFAIP3.

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