Functional TLR9 modulates bone marrow B cells from rheumatoid arthritis patients

Eur J Immunol. 2009 May;39(5):1211-20. doi: 10.1002/eji.200838617.


TLR9 recognizes unmethylated CpG-rich, pathogen-derived DNA sequences and represents the component of the innate immune system that heavily influences adaptive immunity and may contribute to the immunological disturbances in rheumatoid arthritis (RA). Accumulating data indicate that BM of RA patients participates in the pathogenesis of this disease as a site of proinflammatory cytokines overproduction and lymphocytes activation. Here, we investigated the functionality of TLR9 and its role in the modulation of RA BM B-cell functions. We report that BM B cells isolated from RA patients express TLR9 at the mRNA and protein levels acquired at the stage of preB/immature B-cell maturation. Stimulation of BM CD20(+) B cells by CpG-containing oligodeoxynucleotide-enhanced expression of activation markers (CD86 and CD54) triggered IL-6 and TNF-alpha secretion and cell proliferation. Significantly higher levels of eubacterial DNA encoding 16S-rRNA were found in BM samples from RA than osteoarthritis patients. Moreover, RA BM B cells exerted higher expression of CD86 than their osteoarthritis counterparts, suggesting their in situ activation via TLR9. Thus, our data indicate that TLR9 may participate in direct activation and proliferation of B cells in BM, and therefore could play a role in the pathogenesis of RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • B7-2 Antigen / biosynthesis
  • B7-2 Antigen / genetics
  • B7-2 Antigen / immunology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / immunology*
  • Cell Proliferation / drug effects
  • Female
  • Flow Cytometry
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / immunology
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Oligodeoxyribonucleotides / pharmacology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / biosynthesis
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / immunology*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation


  • B7-2 Antigen
  • CPG-oligonucleotide
  • Interleukin-6
  • Oligodeoxyribonucleotides
  • RNA, Messenger
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1