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 journalArticle

1 Citation (Scopus)

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)
JournalKidney International
DOIs
StateAccepted/In press - Jan 1 2018

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B-Cell Activating Factor
Lupus Nephritis
B-Lymphocytes
Systemic Lupus Erythematosus
Autoantibodies
Transgenic Mice
Toll-Like Receptor 7
Interleukin-4 Receptors
RNA
Membranoproliferative Glomerulonephritis
Kidney
Albuminuria
Tumor Necrosis Factor Receptors
Autoantigens
Antigen-Antibody Complex
Autoimmunity
Anti-Idiotypic Antibodies
Cell Survival
Animal Models
Pathology

Keywords

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

ASJC Scopus subject areas

  • Nephrology

Cite this

Arkatkar, T., Jacobs, H. M., Du, S. W., Li, Q. Z., Hudkins, K. L., Alpers, C. E., ... Jackson, S. W. (Accepted/In press). TACI deletion protects against progressive murine lupus nephritis induced by BAFF overexpression. Kidney International. https://doi.org/10.1016/j.kint.2018.03.012

TACI deletion protects against progressive murine lupus nephritis induced by BAFF overexpression. / Arkatkar, Tanvi; Jacobs, Holly M.; Du, Samuel W.; Li, Quan Zhen; Hudkins, Kelly L.; Alpers, Charles E.; Rawlings, David J.; Jackson, Shaun W.

In: Kidney International, 01.01.2018.

Research output: Contribution to journalArticle

Arkatkar, Tanvi ; Jacobs, Holly M. ; Du, Samuel W. ; Li, Quan Zhen ; Hudkins, Kelly L. ; Alpers, Charles E. ; Rawlings, David J. ; Jackson, Shaun W. / TACI deletion protects against progressive murine lupus nephritis induced by BAFF overexpression. In: Kidney International. 2018.
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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.",
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AB - 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.

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