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Abstract Number: 7

Activation of Immature, Transitional B cells by Integrated BCR, TLR and TACI signals promotes systemic autoimmunity in high BAFF settings

Holly Jacobs, Samuel Du, Tanvi Arkatkar and Shaun Jackson, Seattle Children's Research Institute, Seattle, WA

Meeting: 2017 Pediatric Rheumatology Symposium

Keywords: B cells, BAFF, Lupus, TACI and toll-like receptors

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Session Information

Date: Friday, May 19, 2017

Session Title: Plenary Abstract Session 2

Session Type: Abstract Submissions

Session Time: 2:00PM-3:00PM

Background/Purpose:

B cell activating factor of the TNF family (BAFF, also known as BLyS) promotes B cell survival and activation by binding distinct B cell surface receptors, namely BAFF receptor (BAFF-R) and Transmembrane activator and CAML interactor (TACI). Although increased BAFF levels have been implicated in the pathogenesis of SLE, how excess BAFF promotes breaks in B cell tolerance is not completely understood. Since BAFF-R deletion results in loss of mature B cells, BAFF-R-dependent signals were presumed to explain BAFF-mediated autoimmunity. However, we made the surprising observation that B cell TACI signals are critical for BAFF-driven autoantibody production.

Methods:

To test the requirement for B cell receptor (BCR) and Toll-like receptor (TLR) signals in TACI-dependent autoantibody production, we crossed Btk-/-, Myd88-/-, Tlr7-/- and Taci-/-strains with transgenic mice over-expressing BAFF (BAFF-Tg).

Results:

Despite prior studies suggesting that TACI signals negatively regulate B cell activation, we observed that TACI deletion results in a striking loss of class-switched autoantibodies and protection from immune-complex glomerulonephritis in BAFF-Tg mice. Importantly, lack of autoimmunity was not explained by alterations in peripheral B cell development, since both BAFF-Tg and Taci-/-.BAFF-Tg mice exhibited similar B cell hyperplasia. Rather, whereas surface TACI expression is usually limited to mature B cells, we discovered that excess BAFF promotes increased TACI by an activated subset of developing transitional B cells. This novel TACIhi transitional population exhibits an activated, cycling phenotype, is enriched for autoreactive BCR specificities and directly contributes to class-switched autoantibody formation in BAFF-Tg mice. To dissect the B cell-intrinsic signals required for transitional B cell TACI expression and autoantibody production, we crossed BAFF-Tg animals with mice deficient in the B cell signalling adaptor Bruton’s tyrosine kinase (Btk). Notably, Btk-/-.BAFF-Tg exhibited abrogated serum autoantibodies which correlated with loss of surface TACI on transitional B cells. In contrast, despite previous studies reporting a requirement for B cell-intrinsic TLR signals in BAFF-driven autoimmunity, deletion of either the TLR adaptor Myd88 or the endosomal RNA receptor TLR7 exerted no impact on transitional TACI expression. Rather, deletion B cell TLR signals exerted an isolated impact on transitional B cell class-switch recombination, without impacting BCR-dependent TACI upregulation; findings identifying distinct contributions of BCR and TLR signalling pathways to BAFF-driven autoantibody production.

Conclusion:

Our combined findings advance our understanding of how integrated B cell signals promote humoral autoimmunity, by highlighting a novel mechanism in which increased BAFF drives TACI-dependent activation of developing transitional B cells. In addition to informing the genesis of SLE, these findings are likely of particular relevance to the understanding of disease relapse after B cell-depletion with Rituximab; a state characterized by B cell reconstitution within a high BAFF environment.


Disclosure: H. Jacobs, None; S. Du, None; T. Arkatkar, None; S. Jackson, None.

To cite this abstract in AMA style:

Jacobs H, Du S, Arkatkar T, Jackson S. Activation of Immature, Transitional B cells by Integrated BCR, TLR and TACI signals promotes systemic autoimmunity in high BAFF settings [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 4). https://acrabstracts.org/abstract/activation-of-immature-transitional-b-cells-by-integrated-bcr-tlr-and-taci-signals-promotes-systemic-autoimmunity-in-high-baff-settings/. Accessed June 1, 2023.
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