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TLR7, a third signal for the robust generation of spontaneous germinal center B cells in systemic lupus erythematosus

Cellular & Molecular Immunology volume 15, pages 286–288 (2018)Cite this article

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of tolerance to self-nuclear antigens, in which altered B-cell signaling shows an essential role.1 The clonal expansion and antigen-based affinity maturation of B cells primarily occurs at germinal centers (GCs).2 Significantly, recent studies have demonstrated that the robust activity of GCs and the breach of tolerance to self-nuclear antigens are associated with the pathogenesis of SLE.3, 4, 5 Spontaneous GCs (Spt-GCs) can arise in the absence of purposeful immunizations or overt infection and are detected in mice strains with or without autoimmune phenotypes, as well as in human SLE.3, 4, 5 However, the size and the somatic hypermutation frequency of Spt-GCs were shown to be augmented in autoimmune-prone mice, leading to the development of class-switched pathogenic antibodies that drive autoantibody-mediated immune diseases.5 These data suggest that robust Spt-GC is one of the major abnormal sites contributing to the pathogenesis of SLE. It is well accepted that to initiate successful GC formation, at least two signal inductions are needed: engagement with an antigen by naive B cells and the presentation of an antigen by the B cells to Tfh cells, which, in turn, form B-Tfh conjugations.2 In this paper, the activation of Toll-like receptor 7 (TLR7) is proposed and discussed as the third signal for the robust generation of Spt-GC B cells in SLE.

TLR7 is an endosomal TLR that recognizes single-stranded RNA, leading to the activation of innate or adaptive immunity. It was reported that B-cell-intrinsic TLR7 has a pivotal role in the development of SLE.6 In fact, B-cell-intrinsic TLR7 signaling is an essential factor for the formation and responses of Spt-GCs in both autoimmune and non-autoimmune conditions.5, 6 For example, the formation of Spt-GC and the production of auto-antibodies can be driven by the activation of B-cell-intrinsic TLR7 in lupus models,3 but lupus-prone Sle1b mice with a TLR7-KO genotype failed to form Spt-GC B cells.6 Normal mice exposed to TLR7 agonists exhibited typical lupus features, including the expansion of GCs and the production of auto-antibodies.7 Moreover, murine B cells were induced to proliferate, and this was accompanied by an upregulated level of B-cell co-stimulatory factors, the switch of Ig classes and the secretion of immunoglobulins after TLR7 activation.6, 8 All these studies suggest that TLR7 could drive the pathogenesis of SLE by regulating germinal centers (GCs) formation, while the molecular mechanism underlying this regulation is poorly defined.

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Acknowledgements

This work was supported by the Natural Science Foundation of China (81501403) and the Natural Science Foundation for Young Scholars of Jiangsu Province (BK20150700).

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Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China

    Hongye Fan

  2. INSERM U1170, Institute Gustave Roussy, Villejuif, 94805, France

    Deshan Ren

  3. University of Paris Sud, Orsay, 91400, France

    Deshan Ren

  4. Division of Immunology, The State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, 210093, China

    Yayi Hou

  5. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China

    Yayi Hou

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Correspondence to Yayi Hou.

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Fan, H., Ren, D. & Hou, Y. TLR7, a third signal for the robust generation of spontaneous germinal center B cells in systemic lupus erythematosus. Cell Mol Immunol 15, 286–288 (2018). https://doi.org/10.1038/cmi.2017.123

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