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Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells
  1. Ayumi Yoshizaki1,
  2. Takashi Taniguchi1,
  3. Ryosuke Saigusa1,
  4. Takemichi Fukasawa1,
  5. Satoshi Ebata1,
  6. Hiroko Numajiri1,
  7. Kouki Nakamura1,
  8. Takashi Yamashita1,
  9. Takehiro Takahashi1,
  10. Tetsuo Toyama1,
  11. Yoshihide Asano1,
  12. Thomas F Tedder2,
  13. Shinichi Sato1
  1. 1Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  2. 2Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA
  1. Correspondence to Dr Ayumi Yoshizaki, Department of Dermatology, the University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku 113-8655, Tokyo; ayuyoshi{at}me.com

Abstract

Objective To determine the serum levels of nucleosome in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc.

Methods Serum nucleosome levels in 91 patients with SSc were examined by ELISA. The expression of Toll-like receptor (TLR) 9 in T and B cells was quantified by flow cytometric intracellular protein analysis. The effects of nucleosomes on lymphocytes were also analysed. Moreover, we assessed the effects of nucleosomes on fibrosis, using wild type and CD19-deficient bleomycin-treated mice, an experimental model for human SSc.

Results Serum nucleosome levels were elevated in SSc compared with healthy controls and correlated positively with the extent of skin and pulmonary fibrosis and immunological abnormalities. The retrospective longitudinal analysis showed the serum nucleosome levels to be attenuated during the follow-up period. TLR9, which can be stimulated by nucleosome expression was upregulated in the affected T and B cells of patients with SSc. Moreover, nucleosome stimulation strongly increased interleukin (IL)-4 and IL-17 expression of T cells, B-cell IgG production and proliferation of lymphocytes in SSc compared with those in healthy controls. In bleomycin-induced SSc model mice, serum nucleosome levels were elevated compared with control mice. Furthermore, nucleosomes increased IgG production and proliferation of mouse B cells. Although TLR9 expression was similar between wild type and CD19-deficient splenic B cells, CD19 deficiency reduced these nucleosome effects.

Conclusion These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.

  • Systemic Sclerosis
  • B cells
  • T Cells
  • Cytokines
  • Autoimmunity

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