Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus

Jenks, Scott A.; Cashman, Kevin S.; Zumaquero, Esther; Marigorta, Urko M.; Patel, Anjni; Wang, Xiaoqian; Tomar, Deepak; Woodruff, Matthew C.; Simon, Zoe; Bugrovsky, Regina; Blalock, Emily L.; Scharer, Christopher D.; Tipton, Christopher; Wei, Chungwen; Lim, Sei-Young; Petri, Michelle; Niewold, Timothy B.; Anolik, Jennifer H.; Gibson, G R; Lee, F. Eun-Hyung; Boss, Jeremy M.; Lund, Frances E.; Sanz, Igñacio

doi:10.1016/j.immuni.2019.12.005

Cited by 156 publications

(377 citation statements)

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“…Consistently, CD11c + Tbet + ABCs were shown to have selected BCR repertoire (79), with more somatic hypermutations than FOB cells but less than GCB cells (80). Our study also provided in vivo data supporting that CD11c + Tbet + ABC differentiation depends on TLR signaling adaptor MyD88, consistent with the previous finding that IL-21 and TLR7 stimulation cooperate to drive Tbet expression (38,39) and that CD11c + Tbet + ABCs are highly responsive to TLR7 stimulation (34,38).…”

Section: Discussionsupporting

confidence: 90%

“…It suggests that excessive autoantibodies and inadequate affinity-matured antigen-specific antibodies observed in these models-2 seemly paradoxical humoral immune defects-is mechanistically linked by excessive CD11c + Tbet + ABCs. The impact of CD11c + Tbet + ABCs on GC selection and AAM observed in our study is distinct from that on autoimmunity described previously (33)(34)(35)(36)38) and confirmed in this study. Nevertheless, it appears that their ability to promote T-cell activation and T FH differentiation may explain these distinct impacts, as excessive T FH cells have also been proposed to drive the development of spontaneous GCs associated with autoimmunity (23,24).…”

Section: Discussionsupporting

confidence: 76%

“…Several studies have shown that ABCs produce autoantibodies upon stimulation, and that inhibition of ABC differentiation by ablating Tbet prevents autoantibody production in mice (33)(34)(35)(36)(37), including our study in a lupus-like cGVHD model (35). In human, CD11c + Tbet + B cells are linked to autoantibody-producing plasma cells (38). Toll-like receptor (TLR) agonists and BCR crosslinking, in addition to IFNγ and IL-21 signalings, have been suggested to synergize to promote ABC differentiation (39,40).…”

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confidence: 66%

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Excessive CD11c ⁺ Tbet ⁺ B cells promote aberrant T _FH differentiation and affinity-based germinal center selection in lupus

Zhang

Liu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ABCs and deregulated TFHcell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ABC differentiation, and blocking CD11c+Tbet+ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFHcell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 66%

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Excessive CD11c ⁺ Tbet ⁺ B cells promote aberrant T _FH differentiation and affinity-based germinal center selection in lupus

Zhang

Liu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Although both TLR2 and TLR7 are preferentially expressed by intra-graft B cells, we found no difference between intrarenal and tonsil B cells in the overall expression of 26 genes associated with DN cells (Arazi et al, 2019;Jenks et al, 2018) (Supplementary Figure 3A). Therefore, although DN cells and our intrarenal B cells share high expression of innate immune genes, otherwise they have distinct phenotypes.…”

Section: Distinct Transcriptional States In Activated Intrarenal Andmentioning

confidence: 74%

Intrarenal B cells integratein situinnate and adaptive immunity in human renal allograft rejection

Asano

Daccache

Jain

et al. 2020

Preprint

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In human allograft rejection, intrarenal B cell infiltrates identify those with a poor prognosis. However, how intrarenal B cells contribute to rejection is not known. Single cell RNA-sequencing of intrarenal class-switched B cells revealed a unique innate cell transcriptional state resembling murine peritoneal B1 cells (Bin cells). Comparison to the transcriptome of whole renal allograft rejecting tissue revealed that Bin cells existed within a complex autocrine and paracrine network of signaling axes. The immunoglobulins expressed by Bin cells did not bind donor specific antigens nor were they enriched for reactivity to ubiquitously expressed self-antigens. Rather, Bin cells frequently expressed antibodies reactive with renal expressed antigens. Furthermore, local antigens could drive Bin cell proliferation and differentiation into plasma cells expressing self-reactive antibodies. By contributing to local innate immune networks, and expressing antibodies reactive with renal expressed antigens, Bin cells are predicted to amplify local inflammation and tissue destruction.

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“…A previous study reported increased frequency of DN B cells in SLE patients, which correlated to higher SLEDAI scores and elevated anti-dsDNA and anti-Sm antibodies in circulation 27 . Other studies have identified an aberrant CD19 + IgD − CD27 − CXCR5 − B cell subset in SLE patients, which is closely associated with the inflammatory changes characteristic of the disease 34,35 . In agreement with our findings, Kubo et al 36 also detected increased proportion of both the DN and PC subsets in SLE patients compared to the healthy controls.…”

Section: Discussionmentioning

confidence: 96%

Aberrant expression of PD-1 on B cells and its association with the clinical parameters of systemic lupus erythematosus

Lü

Zhu

et al. 2020

Preprint

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Background: Programmed death 1 (PD-1) is an immunoregulatory receptor that inhibits T cell activation and proliferation upon binding to its cognate ligand (PD-L1). However, the role of the PD-1/PD-L1 axis in B cell function, especially in inflammatory and autoimmune disorders, is less clear. The aim of this study was to analyze the PD-1 expression patterns on multiple B cell subpopulations isolated from systemic lupus erythematosus (SLE) patients, and determine their clinical relevance. Results: The frequency of B cells increased significantly in patients with active SLE compared with healthy controls and patients with inactive SLE. In particular, the frequencies of the IgD CD27 and IgD CD27high (plasmablast cells) subpopulations were significantly higher in the patients compared to healthy individuals. Interestingly, the patients with active SLE harbored an increased proportion of the PD-1+ B cells, which correlated significantly with the disease severity (SLEDAI scores), incidence of lupus nephritis, and the circulating levels of autoantibodies and complement factors. Furthermore, the primary PD-1+ B cells isolated from the peripheral blood of SLE patients proliferated faster and secreted more anti-dsDNA antibodies and immunoglobulins in vitro compared to the PD-1+/- B cells from healthy controls. Conclusions: PD-1 is overexpressed on all B cell subpopulations of SLE patients and associated with disease progression.

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Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus

Cited by 156 publications

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Excessive CD11c ⁺ Tbet ⁺ B cells promote aberrant T _FH differentiation and affinity-based germinal center selection in lupus

Excessive CD11c ⁺ Tbet ⁺ B cells promote aberrant T _FH differentiation and affinity-based germinal center selection in lupus

Intrarenal B cells integratein situinnate and adaptive immunity in human renal allograft rejection

Aberrant expression of PD-1 on B cells and its association with the clinical parameters of systemic lupus erythematosus

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Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus

Cited by 156 publications

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Excessive CD11c + Tbet + B cells promote aberrant T FH differentiation and affinity-based germinal center selection in lupus

Excessive CD11c + Tbet + B cells promote aberrant T FH differentiation and affinity-based germinal center selection in lupus

Intrarenal B cells integratein situinnate and adaptive immunity in human renal allograft rejection

Aberrant expression of PD-1 on B cells and its association with the clinical parameters of systemic lupus erythematosus

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Product

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Excessive CD11c ⁺ Tbet ⁺ B cells promote aberrant T _FH differentiation and affinity-based germinal center selection in lupus

Excessive CD11c ⁺ Tbet ⁺ B cells promote aberrant T _FH differentiation and affinity-based germinal center selection in lupus