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OP0120 Roles of B Cell Leukemia/Lymphoma 3 in The Development of T Follicular Helper Cells and the Pathogenesis of Rheumatoid Arthritis
  1. K. Meguro1,
  2. K. Suzuki1,
  3. J. Hosokawa1,
  4. Y. Sanayama1,
  5. S. Tanaka1,
  6. S. Furuta1,
  7. K. Ikeda1,
  8. H. Takatori1,
  9. A. Suto1,
  10. O. Ohara2,
  11. H. Nakajima1
  1. 1Allergy and Clinical Immunology, Chiba University
  2. 2Technology Development, Kazusa DNA Research Institute, Chiba, Japan

Abstract

Background Rheumatoid arthritis (RA) is a chronic inflammatory disease and proinflammatory cytokines such as TNFα and IL-6 play critical roles in the pathogenesis of RA. The blockade of IL-6 signaling by Tocilizumab (TCZ) has shown the clinical efficacy for patients with RA. To clarify the roles of IL-6 signaling in CD4+ T cells in the pathogenesis of RA, we previously compared gene expression profiles of CD4+ T cells by DNA microarray analysis before and after the treatment with TCZ in RA patients who exhibited good clinical responses to the treatment (1, 2), and identified that B cell leukemia/lymphoma 3 (Bcl3), an IκB family member, was down-regulated by TCZ therapy (1). However, the role of Bcl3 expressed in CD4+ T cells in the pathogenesis of RA remains unclear.

Objectives The objective of this study is to examine the role of Bcl3 expressed in CD4+ T cells in the pathogenesis of RA.

Methods We compared signal intensity of Bcl3 in CD4+ T cells between untreated RA patients and healthy controls by DNA microarray analysis. We examined the roles of IL-6-STAT3 signaling in Bcl3 induction. We also analyzed gene expression profiles of Bcl3-transduced CD4+ T cells by RNA-sequencing analysis. We examined the effect of enforced expression as well as gene silencing of Bcl3 on the development of T follicular helper (Tfh) cells. Finally, we examined a correlation between signal intensities of Bcl3 and Tfh cell-related genes in CD4+ T cells in untreated RA patients.

Results Bcl3 levels were significantly higher in RA patients than those in healthy controls. IL-6 induced Bcl3 expression in CD4+ T cells in a STAT3-dependent manner. Transcriptome analysis revealed that the expression of Bcl6, a master regulator of Tfh cell differentiation, was significantly upregulated by the enforced Bcl3 expression (Figure1). The enforced Bcl3 expression increased but the Bcl3 silencing decreased IL-21-producing Tfh-like cells. Bcl3 levels were positively correlated with those of Tfh cell-related genes such as CXCR5, ICOS, and ASCL2 in CD4+ T cells in RA patients.

Conclusions Bcl3 is involved in the development of Tfh cells and the pathogenesis of RA presumably by inducing IL-21 production.

References

  1. Saito Y, Kagami SI, Sanayama Y, Ikeda K, Suto A, Kashiwakuma D, et al. AT-rich interactive domain-containing protein 5a functions as a negative regulator of RORγt-induced Th17 cell differentiation. Arthritis Rheum. 2014;66(5):1185-94.

  2. Sanayama Y, Ikeda K, Saito Y, Kagami S, Yamagata M, Furuta S, et al. Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray. Arthritis Rheum. 2014;66(6):1241-31.

Disclosure of Interest K. Meguro: None declared, K. Suzuki: None declared, J. Hosokawa: None declared, Y. Sanayama: None declared, S. Tanaka: None declared, S. Furuta: None declared, K. Ikeda: None declared, H. Takatori: None declared, A. Suto: None declared, O. Ohara: None declared, H. Nakajima Grant/research support from: Chugai Pharmaceutical Co., Ltd, Bristol-Myers Squibb, and Mitsubishi Tanabe Pharma Co.

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