title: Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells.
abstract: To determine the serum levels of nucleosome in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshizaki
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Saigusa
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takemichi
authors.initials: T
authors.lastname: Fukasawa
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ebata
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Numajiri
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Toyama
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.affiliation: Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001761:Bleomycin; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D009707:Nucleosomes / Q000378:metabolism*; D012189:Retrospective Studies; D012595:Scleroderma, Systemic / Q000097:blood* / Q000139:chemically induced / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D020381:Interleukin-17; D009707:Nucleosomes; D051217:Toll-Like Receptor 9; D001761:Bleomycin; D015847:Interleukin-4
keywords: Autoimmunity; B cells; Cytokines; Systemic Sclerosis; T Cells