Elsevier

Journal of Autoimmunity

Volume 61, July 2015, Pages 9-16
Journal of Autoimmunity

Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

https://doi.org/10.1016/j.jaut.2015.04.007Get rights and content

Highlights

  • Loss of TACI expression fully protects BAFF Tg chimera mice from SLE.

  • TACI signalling upregulates TLR7 expression in B cells.

  • Biologics targeting TACI may treat autoimmunity without depleting B cells.

Abstract

B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.

Introduction

B cell-activation factor of the tumor necrosis factor superfamily (BAFF; also named BLyS, TNFSF13b) is an essential survival and maturation factor for B cells (reviewed in Ref. [1]). However, excessive BAFF production in BAFF transgenic (Tg) mice leads to the development of an autoimmune disease resembling systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) and characterized by the production of a wide range of autoantibodies (reviewed in Ref. [1]). Moreover, elevated BAFF levels have been detected in the serum of patients suffering from various autoimmune conditions, such as SLE, primary SS, and rheumatoid arthritis (RA) [1]. In March 2011, belimumab (trade name Benlysta®), a BAFF neutralizing antibody, was approved for use in a subset of patients with SLE (reviewed in Ref. [2]), highlighting the major importance of BAFF in this pathology.

Indeed, the current view supporting B cell number reduction in SLE relies on the notion that the excessive production of BAFF observed in SLE patients is likely linked to the aberrant survival of self-reactive B cells that would normally die throughout the course of B cell tolerance, had they not received excessive survival signals through BAFF receptor (BAFF-R) [2]. Previous studies from our group have shown that excessive BAFF production does not corrupt negative selection of strongly self-reactive B cells, but rather, excess BAFF allows the expansion of low affinity self-reactive B cells that are normally found in the healthy B cell repertoire [3]. As these low affinity self-reactive B cells mostly populate the marginal zone (MZ) and B-1 compartments where self-reactive B cells are known to naturally accumulate, an alternative explanation for disease in BAFF Tg mice has emerged, suggesting that excessive pro-inflammatory autoantibody production by innate B cells, rather than uncontrolled B cell survival, underlies the autoimmune disorders developing in BAFF Tg mice [4], [5].

Interestingly, rituximab (an anti-human CD20 B cell depleting antibody) is more effective at reducing B cell numbers than belimumab (reviewed in Ref. [6]), however, rituximab's efficacy in treating SLE remains debated (reviewed in Ref. [7]). This difference suggests the possibility that a function other than inhibition of B cell survival may have contributed to the efficacy of belimumab. One possibility is a role for BAFF inhibition in preventing autoantibody production, which is an amelioration that has been noted in SLE patients responding to belimumab (reviewed in Ref. [2]).

Apart from BAFF-R, BAFF binds to at least three other receptors: transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI, TNFRSF13b) and B cell maturation antigen (BCMA, TNFRSF17), and possibly Nogo-66 receptor [8]. BCMA is mostly expressed on plasma cells (PC) and is important for their survival, essentially in response to a proliferation-inducing ligand (APRIL; also named TNFSF13), which binds to TACI and BCMA (reviewed in Ref. [9]). TACI is expressed on mature B cells, and most highly on MZ and peritoneal B-1 B cells in mice; TACI is expressed most highly on CD19+/CD27+ memory B cells in humans [10], [11]. TACI expression is also upregulated on B cells of SLE patients [12]. Studies using TACI-deficient mice revealed that TACI has a dual role; TACI is essential for the production of antibodies in response to T-independent antigens but is also critical for the maintenance of B cell homeostasis (reviewed in Ref. [1]).

TLRs, particularly TLR9 and TLR7, are thought to play a pathogenic role in SLE (reviewed in Ref. [13]); we have previously shown that activation of TLR9 or TLR7 strongly upregulates TACI expression on B cells and that BAFF stimulation of B cells also upregulates TLR9 and TLR7 in these cells [5]. Moreover, we also showed that expression of MyD88 in B cells, a signaling element downstream of TLR7 and TLR9 (as well as TLR2, TLR4, TLR5 and IL-1R), is critical for disease progression in BAFF Tg mice [5]. TACI interacts directly with MyD88, establishing a tight connection between TACI activation and TLR signaling and function [14]. TACI also forms a complex with the activated (cleaved) forms of TLR7 or TLR9, and TACI signals synergize with those of TLR7 and TLR9 in B cells [15].

Considering that BAFF-mediated disease is T cell-independent [5] and that TACI is an essential receptor for T-independent B cell responses with its function closely associated with that of TLRs [1], the possibility emerged that the efficacy behind BAFF inhibition in the clinic may lie in the loss of BAFF signals via TACI rather than loss of a fraction of B cells. Indeed, the work presented here demonstrates that loss of TACI in BAFF Tg mice fully protects the animals against autoantibody production and severe SLE-like pathologies, without having any impact on B cell survival.

Section snippets

Mice

BAFF Tg mice that overexpress murine BAFF behind a liver-specific α1-antitrypsin promoter (MGI: 2386944) [16] and TACI−/− mice on a C57BL/6 background have been described previously (MGI: 2182823) [17]. C57BL/6 mice were used as WT controls in all experiments. All mice used in this study were females. Mice were housed under conventional barrier protection and handled in accordance with the guidelines of our institutional ethics committees, in compliance with the Australian Code of Practice for

BAFF-mediated upregulation of TLR7 expression in B cells requires TACI signaling

Our previous work has shown that TLR7 activation of B cells strongly upregulates the expression of the BAFF receptor TACI [5]. We show here that conversely, BAFF stimulation of B cells upregulates TLR7 expression in a TACI-dependent manner, as TACI−/− B cells failed to significantly upregulate TLR7 expression in response to stimulation with BAFF (Fig. 1A). Further supporting these findings, TACI−/− MZ and follicular (Fo) B cells express significantly less TLR7 than WT controls, whereas

Discussion

Our work demonstrates a central and unappreciated role for the BAFF receptor TACI in driving autoantibody production and autoimmune tissue damage in response to excessive BAFF signaling. Our results challenge previous views that excessive B cell survival is the major event underpinning loss of B cell homeostasis and resulting autoimmunity in BAFF Tg mice, and in SLE patients with high BAFF levels [3]. Historically, this original notion has supported strategies aimed at reducing B cell

Conclusions

Our work provides critical new information on the mechanism of action of BAFF in SLE. Hematopoietic-specific deletion of TACI expression in a mouse model of SLE resulted in complete protection from autoantibody production and organ pathology without extensive loss of B cells; therefore, we suggest that limiting TACI signaling in SLE may specifically target autoantibody generation, which unlike B cell-depleting agents is likely to preserve important protective functions of B cells. While B

Disclosures

The authors have no financial conflicts of interest.

Acknowledgments

This work was supported by the National Health and Medical Research Council and Victorian State Government Operational Infrastructure Support. JW-B and FM are Senior Research Fellows of the NHMRC. We thank M. Hibbs, F. Vincent and E. McAllister for review of the manuscript. We thank M. Le Page, Z. Nasa, M. Fuchsberger, M. Bijker, H. McGuire, R. Stokes, A. Nguyen, T. Nguyen, and J. Kang for technical assistance. The authors acknowledge the facilities and scientific and technical assistance of

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