Session Type: Abstract Submissions
Session Time: 2:00PM-3:00PM
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.
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).
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.
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.
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). http://acrabstracts.org/abstract/activation-of-immature-transitional-b-cells-by-integrated-bcr-tlr-and-taci-signals-promotes-systemic-autoimmunity-in-high-baff-settings/. Accessed May 1, 2017.
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ACR Meeting Abstracts - http://acrabstracts.org/abstract/activation-of-immature-transitional-b-cells-by-integrated-bcr-tlr-and-taci-signals-promotes-systemic-autoimmunity-in-high-baff-settings/