TACI deletion protects against progressive murine lupus nephritis induced by BAFF overexpression

Tanvi Arkatkar, Holly M. Jacobs, Samuel W. Du, Quan Zhen Li, Kelly L. Hudkins, Charles E. Alpers, David J. Rawlings, Shaun W. Jackson

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)728-740
Number of pages13
JournalKidney international
Volume94
Issue number4
DOIs
StatePublished - Oct 2018

Keywords

  • B-cell activating factor of the TNF family (BAFF)
  • autoantibodies
  • lupus nephritis
  • systemic lupus erythematosus
  • transmembrane activator and CAML interactor (TACI)

ASJC Scopus subject areas

  • Nephrology

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