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

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

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
2
Boston University School of Medicine, Boston, MA 02118, USA.
3
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10129, USA.
4
Department of Respiratory, Inflammation and Autoimmunity (RIA), MedImmune LLC, Gaithersburg, MD 20878, USA.
5
Department of Cancer Biology, MedImmune LLC, Gaithersburg, MD 20878, USA.
6
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: michael.carroll@childrens.harvard.edu.

Abstract

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

PMID:
28099860
DOI:
10.1016/j.immuni.2016.12.014
[Indexed for MEDLINE]
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