@article{1144a3bb0d0241dc83a239db2d9e5872,
title = "TACI deletion protects against progressive murine lupus nephritis induced by BAFF overexpression",
abstract = "B cells are known to promote the pathogenesis of systemic lupus erythematosus (SLE) via the production of pathogenic anti-nuclear antibodies. However, the signals required for autoreactive B cell activation and the immune mechanisms whereby B cells impact lupus nephritis pathology remain poorly understood. The B cell survival cytokine B cell activating factor of the TNF Family (BAFF) has been implicated in the pathogenesis of SLE and lupus nephritis in both animal models and human clinical studies. Although the BAFF receptor has been predicted to be the primary BAFF family receptor responsible for BAFF-driven humoral autoimmunity, in the current study we identify a critical role for signals downstream of Transmembrane Activator and CAML Interactor (TACI) in BAFF-dependent lupus nephritis. Whereas transgenic mice overexpressing BAFF develop progressive membranoproliferative glomerulonephritis, albuminuria and renal dysfunction, TACI deletion in BAFF-transgenic mice provided long-term (about 1 year) protection from renal disease. Surprisingly, disease protection in this context was not explained by complete loss of glomerular immune complex deposits. Rather, TACI deletion specifically reduced endocapillary, but not mesangial, immune deposits. Notably, although excess BAFF promoted widespread breaks in B cell tolerance, BAFF-transgenic antibodies were enriched for RNA- relative to DNA-associated autoantigen reactivity. These RNA-associated autoantibody specificities were specifically reduced by TACI or Toll-like receptor 7 deletion. Thus, our study provides important insights into the autoantibody specificities driving proliferative lupus nephritis, and suggests that TACI inhibition may be novel and effective treatment strategy in lupus nephritis.",
keywords = "B-cell activating factor of the TNF family (BAFF), autoantibodies, lupus nephritis, systemic lupus erythematosus, transmembrane activator and CAML interactor (TACI)",
author = "Tanvi Arkatkar and Jacobs, {Holly M.} and Du, {Samuel W.} and Li, {Quan Zhen} and Hudkins, {Kelly L.} and Alpers, {Charles E.} and Rawlings, {David J.} and Jackson, {Shaun W.}",
note = "Funding Information: Notably, several animal and human studies support the concept that RNA-associated autoantibodies promote the pathogenesis of lupus nephritis. For example, in murine lupus models, deletion of TLR7, an endosomal single-stranded RNA receptor, results in the loss of RNA-associated autoantibodies and protection from IC glomerulonephritis. In contrast, deletion of TLR9, a DNA-binding receptor recognizing unmethylated CpG dinucleotides, resulted in a surprising increase in systemic inflammation despite the loss of kinetoplast-reactive anti-dsDNA autoantibodies. 18,24 Additional support for a role for RNA-associated autoantibodies in murine lupus nephritis is provided by the pristine-induced lupus model, in which interleukin-12 deletion protects against IC glomerulonephritis without impacting anti-dsDNA titers. Although these interleukin-12–dependent effects were attributed to the loss of T Funding Information: The authors thank Julia Proctor, Jit Khim, and Karen Sommer for assistance with murine studies and laboratory management and Daryl Okamura for valuable suggestions and discussions. This work was supported by the National Institutes of Health under award numbers DP3-DK097672 (DJR), DP3-DK111802 (DJR), R01AI071163 (DJR), R21AI123818 (DJR), and K08AI112993 (SWJ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support provided by the Children's Guild Association Endowed Chair in Pediatric Immunology (DJR), the Benaroya Family Gift Fund (DJR), the ACR REF Rheumatology Career Development K Supplement (SWJ), the Arthritis National Research Foundation (ANRF) Eng Tan Scholar Award (SWJ), and the Arnold Lee Smith Endowed Professorship for Research Faculty Development (SWJ). Funding Information: Notably, several animal and human studies support the concept that RNA-associated autoantibodies promote the pathogenesis of lupus nephritis. For example, in murine lupus models, deletion of TLR7, an endosomal single-stranded RNA receptor, results in the loss of RNA-associated autoantibodies and protection from IC glomerulonephritis. In contrast, deletion of TLR9, a DNA-binding receptor recognizing unmethylated CpG dinucleotides, resulted in a surprising increase in systemic inflammation despite the loss of kinetoplast-reactive anti-dsDNA autoantibodies. 18,24 Additional support for a role for RNA-associated autoantibodies in murine lupus nephritis is provided by the pristine-induced lupus model, in which interleukin-12 deletion protects against IC glomerulonephritis without impacting anti-dsDNA titers. Although these interleukin-12–dependent effects were attributed to the loss of TH1-biased inflammation, RNP autoantibodies were strikingly reduced by interleukin-12 deletion, and these events correlated with the loss of capillary, but not mesangial, IC deposits,44 observations mirroring the renal pathology of Taci–/–.BAFF-Tg mice. Consistent with these previous data, we now report that BAFF-Tg sera are enriched for RNA-associated autoantibodies, that deletion of either TACI or TLR7 results in loss of these autoantibody specificities, and that this change in the autoantibody repertoire correlates with the lack of endocapillary immune deposits and protection from BAFF-driven renal disease. Publisher Copyright: {\textcopyright} 2018 International Society of Nephrology",
year = "2018",
month = oct,
doi = "10.1016/j.kint.2018.03.012",
language = "English (US)",
volume = "94",
pages = "728--740",
journal = "Kidney international",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "4",
}