TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease

Jane A. Gross (), Janet Johnston, Sherri Mudri, Rachel Enselman, Stacey R. Dillon, Karen Madden, Wenfeng Xu, Julia Parrish-Novak, Don Foster, Cathy Lofton-Day, Margaret Moore, Alisa Littau, Angelika Grossman, Harald Haugen, Kevin Foley, Hal Blumberg, Kim Harrison, Wayne Kindsvogel and Christopher H. Clegg
Additional contact information
Jane A. Gross: Departments of Immunology
Janet Johnston: Departments of Immunology
Sherri Mudri: Departments of Immunology
Rachel Enselman: Departments of Immunology
Stacey R. Dillon: Departments of Immunology
Karen Madden: Functional Cloning
Wenfeng Xu: Functional Cloning
Julia Parrish-Novak: Functional Cloning
Don Foster: Functional Cloning
Cathy Lofton-Day: Genetics, ZymoGenetics
Margaret Moore: Genetics, ZymoGenetics
Alisa Littau: in Vivo Biology
Angelika Grossman: in Vivo Biology
Harald Haugen: in Vivo Biology
Kevin Foley: Genetics, ZymoGenetics
Hal Blumberg: Genetics, ZymoGenetics
Kim Harrison: Departments of Immunology
Wayne Kindsvogel: Departments of Immunology
Christopher H. Clegg: Departments of Immunology

Nature, 2000, vol. 404, issue 6781, 995-999

Abstract: Abstract B cells are important in the development of autoimmune disorders by mechanisms involving disregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK)1,2,3,4,5 is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo1,2,5. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-1a lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI6 and BCMA7,8, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI–Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI–Ig as a promising treatment of autoimmune disease in humans.

Date: 2000
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DOI: 10.1038/35010115

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