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AB0244 MIR-155 Expression in B Cells of Rheumatoid Arthritis Patients Is Related To Follicular Synovitis and Mirrors B Cell Subpopulations Changes after IL-6R Inhibitor Treatment
  1. S. Alivernini1,
  2. B. Tolusso1,
  3. L. Petricca1,
  4. M. Kurowska-Stolarska2,
  5. A.L. Fedele1,
  6. E. Gremese1,
  7. G. Di Sante3,
  8. I.B. McInnes2,
  9. G. Ferraccioli1
  1. 1Institute of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
  2. 2Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
  3. 3Institute of General Pathology, Catholic University of the Sacred Heart, Rome, Italy

Abstract

Background MicroRNA-155 (miR-155) was shown to be a key regulator of B cell biology. The fine-tuning of the transcription factor PU.1 by miR-155 is required for high-affinity IgG1 production and B cell maturation. However, the role of miR-155 in the activation of B cells in Rheumatoid Arthritis (RA) has not been explored.

Objectives To investigate miR-155 expression in RA B cells and its association with B cell subpopulations distribution, synovial histological pattern and anti-IL6R treatment response.

Methods 42 RA patients naive to treatment who underwent synovial tissue (ST) biopsy were enrolled and 30 RA no responder to MTX (MTX-IR) and 15 Osteoarthritis (OA) patients were used as comparison. Based on immunostaining for CD68, CD21, CD3 and CD20 cells, ST samples were categorized as diffuse or follicular pattern. CD19+ cells were isolated from peripheral blood (PB) and B cells subpopulations were assessed by FACS using IgD/CD27 classification. In 14 MTX-IR ERA patients starting TCZ (8 mg/kg), PB-derived CD19+ cells were tested for B cells subpopulations at baseline and after 3–6 and 12 months in association with miR-155 and PU.1 expression by qPCR. IL-6 receptor (IL6-R) was experimentally confirmed as miR-155 target by Luciferase assay. PB-derived CD19+ cells of HC were stimulated with IL-6 (20 pg/mL) and miR-155 expression was checked after 24–48 and 72h respectively.

Results At study entry, naive RA and MTX-IR patients showed higher incidence of follicular synovitis than OA patients (p=0.001 and p=0.002 respectively). Moreover, RA patients with follicular synovitis were more likely ACPA positive (p=0.001) compared to patients with diffuse pattern. At baseline, PB derived B cells of RA patients were characterized by higher IgDCD27 cells (p=0.05) percentages compared to HC. Moreover, PB-derived CD19+ cells of RA patients with follicular synovitis showed an activated memory phenotype compared to patients with diffuse pattern (p=0.01). Finally, PB-derived CD19+ cells of naive and MTX-IR RA patients with follicular synovitis showed significantly higher expression of miR-155 compared to HC (p=0.001 and p=0.002 respectively) mainly in ACPA positive patients (p=0.001). During IL-6R inhibitor treatment, we found that IgDCD27 cells percentage significantly decreases after 12 months (p<0.05) follow-up compared to baseline. miR-155 expression in PB-derived CD19+ cells was significantly down-regulated after 3 (p=0.01), 6 (p=0.002) and 12 (p=0.001) months of TCZ treatment respectively. Conversely, PU.1 expression in PB-derived CD19+ cells was significantly up-regulated after 12 months (p=0.04) of TCZ treatment. Finally, miR-155 was found to be an inducible miR after IL-6 stimulation (p<0.05).

Conclusions B-cells of naïve and MTX-IR RA patients with follicular synovitis show a memory phenotype and a high expression of miR-155 which is related with ACPA positivity. Moreover, miR-155 expression in PB-derived B cells of RA patients significantly decreases during IL-6R inhibitor treatment mirroring the changes of B cell subpopulations distribution. Thus, miR-155 may represent a key regulator of B-cells in RA through IL-6 pathway.

Disclosure of Interest None declared

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