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

Publication date: 17 January 2017
Source:Immunity, Volume 46, Issue 1
Author(s): Abhishek Das, Balthasar A. Heesters, Allison Bialas, Joseph O'Flynn, Ian R. Rifkin, Jordi Ochando, Nanette Mittereder, Gianluca Carlesso, Ronald Herbst, Michael C. Carroll
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.

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Teaser

Follicular dendritic cells (FDCs) maintain germinal centers through the uptake and cycling of complement-opsonized immune complexes. Das et al. show that in a murine model of lupus, uptake of self-immune complexes by FDCs activates TLR7 and that these stromal cells are a critical source of the IFN-α driving autoimmunity.


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