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. 3–5 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. 3–5 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 autoantibodymediated 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-cellintrinsic TLR7 has a pivotal role in the development of SLE. 6 In fact, B-cellintrinsic TLR7 signaling is an essential factor for the formation and responses of Spt-GCs in both autoimmune and nonautoimmune 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 autoantibodies. 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. Autoreactive B cells resulting from GCs that experience class-switch and somatic hypermutation (SHM), are ordinarily induced to death by negative selection. 1 However, the exclusion function of these autoreactive B cells in GCs is defective in both lupus mice 9 and human SLE. 4 Prolonged GC activity could lead to high-affinity antibodies through the extended SHM, but in return, the extended SHM also increases the chance of the appearance of selfreactive variants producing autoantibodies that finally escape the negative affinity selection. 2 The activation of TLR7 has been reported to enhance the persistence of GCs for several months in mice 10 and is involved in the biased selection of the autoreactive B-cell repertoire in lupus-like GCs. 9 In addition, lupus-prone mice deficient in TLR7 abrogated the production of an RNA-specific autoantibody. 5 Moreover, mice deficient in TLR7 signaling exhibit a significant reduction in the GC response upon an RNA virus challenge and have a relatively diminished dark zone, where extensive proliferation and SHM occurs,