Higher-order CpG-DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice

Eur J Immunol. 2006 Jul;36(7):1951-62. doi: 10.1002/eji.200535734.


Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / genetics*
  • Adjuvants, Immunologic / physiology
  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • CpG Islands / genetics
  • CpG Islands / immunology*
  • DNA / physiology*
  • Disease Models, Animal
  • Female
  • Ligands
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lymphocyte Activation / genetics*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Inbred MRL lpr
  • Mice, Inbred NZB
  • Mice, Knockout
  • Oligodeoxyribonucleotides / pharmacology*
  • Toll-Like Receptor 9 / physiology


  • Adjuvants, Immunologic
  • CPG-oligonucleotide
  • Ligands
  • Oligodeoxyribonucleotides
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • DNA