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

Figgett, William A.; Deliyanti, Devy; Fairfax, Kirsten; Quah, Pin Shie; Wilkinson-Berka, Jennifer L.; Mackay, Fabienne

doi:10.1016/j.jaut.2015.04.007

Cited by 43 publications

(45 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since BAFF-R deletion causes loss of peripheral B cells beyond the transitional stage (2), this receptor was anticipated to be the major contributor to the autoimmune phenotype of BAFF-Tg mice. However, a recent study demonstrated that TACI deletion prevents humoral autoimmunity in BAFF-Tg mice (3); an observation we confirm in this current report.…”

Section: Introductionsupporting

confidence: 91%

See 1 more Smart Citation

Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells

Jacobs¹,

Thouvenel²,

Leach³

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear antibodies. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remains unclear. We now report that, whereas surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACIhi transitional cells from BAFF-Tg mice are characterized by an activated, cycling phenotype; and the TACIhi cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase (AID) and T-bet and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACIhi transitional B cells from BAFF-Tg mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism whereby BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells.

show abstract

Section: Introductionsupporting

confidence: 91%

“…1A). In keeping with this idea, Figgett et al recently reported decreased autoimmunity in irradiated BAFF-Tg mice reconstituted with Taci −/− BM (3). Together, these observations demonstrate that TACI is required for development of humoral autoimmunity in BAFF-Tg mice.…”

Section: Resultsmentioning

confidence: 72%

Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells

Jacobs¹,

Thouvenel²,

Leach³

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…This is consistent with previous reports that BAFF is an effective adjuvant for viral and bacterial antigens, including HIV-1 envelope and pneumococcal surface adhesin A (29,30). Our findings dovetail with reports that dampening the BAFF signaling axis is an effective strategy to prevent autoimmune diseases such as arthritis, systemic lupus erythematosus, and type II diabetes by diminishing the antibody production and survival of autoreactive B cells (47)(48)(49). While BAFF in the context of RABV vaccination supports desired B cell responses, we confirmed through monitoring of autoimmune antibodies, specifically serum anti-doublestranded DNA antibody levels, that the transient expression of BAFF did not induce associated autoimmune dysfunction (Fig.…”

Section: Discussionsupporting

confidence: 93%

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

Haley

Tzvetkov

Meuwissen

et al. 2017

J Virol

View full text Add to dashboard Cite

Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP.IMPORTANCE Effective RABV PEP is currently resource-and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality.

show abstract

“…As an alternative explanation, it is also possible that the mechanism by which BAFF induces autoimmunity and GC B cell formation in BAFF Tg mice does not rely on effects on follicular B cells. Supporting this hypothesis, several recent reports indicate that autoimmunity in BAFF Tg mice is T-cell independent [30] and relies on the activation of transitional B cells [45] and/or on the innate activation of B cells via the upregulation of TLRs by TACI expressed preferentially on marginal zone and B1 B cells [31,46]. The latter result is in agreement with the phenotype of expanded B cells in BAFF Tg mice which are mostly of a marginal zone-like phenotype in spleen and salivary glands [25,26].…”

Section: Discussionmentioning

confidence: 89%

BAFF overexpression increases lymphocytic infiltration in Sjögren's target tissue, but only inefficiently promotes ectopic B-cell differentiation

Ding

Zhang

Haskett

et al. 2016

Clinical Immunology

View full text Add to dashboard Cite

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

Cited by 43 publications

References 43 publications

Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells

Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells

Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

BAFF overexpression increases lymphocytic infiltration in Sjögren's target tissue, but only inefficiently promotes ectopic B-cell differentiation

Contact Info

Product

Resources

About