Follicular Dendritic Cell Activation by TLR Ligands Promotes Autoreactive B Cell Responses

Immunity. 2017 Jan 17;46(1):106-119. doi: 10.1016/j.immuni.2016.12.014.


A hallmark of autoimmunity in murine models of lupus is the formation of germinal centers (GCs) in lymphoid tissues where self-reactive B cells expand and differentiate. In the host response to foreign antigens, follicular dendritic cells (FDCs) maintain GCs through the uptake and cycling of complement-opsonized immune complexes. Here, we examined whether FDCs retain self-antigens and the impact of this process in autoantibody secretion in lupus. We found that FDCs took up and retained self-immune complexes composed of ribonucleotide proteins, autoantibody, and complement. This uptake, mediated through CD21, triggered endosomal TLR7 and led to the secretion of interferon (IFN) α via an IRF5-dependent pathway. Blocking of FDC secretion of IFN-α restored B cell tolerance and reduced the amount of GCs and pathogenic autoantibody. Thus, FDCs are a critical source of the IFN-α driving autoimmunity in this lupus model. This pathway is conserved in humans, suggesting that it may be a viable therapeutic target in systemic lupus erythematosus.

Keywords: CD21; CD35; DAMP; TLR7; autoimmunity; follicular dendritic cells; immune complex; interferon-α; systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoantigens / immunology
  • Autoimmunity / immunology*
  • B-Lymphocytes / immunology*
  • Dendritic Cells, Follicular / immunology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Interferon-alpha / biosynthesis
  • Interferon-alpha / immunology
  • Ligands
  • Lupus Erythematosus, Systemic / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Polymerase Chain Reaction
  • Toll-Like Receptor 7 / immunology
  • Transcriptome


  • Autoantigens
  • Interferon-alpha
  • Ligands
  • Toll-Like Receptor 7