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

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) is a member of the tumour necrosis factor (TNF) ligan...

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Bibliographic Details
Published in:Nature (London) 2000-04, Vol.404 (6781), p.995-999
Main Authors: Gross, Jane A, Johnston, Janet, Mudri, Sherri, Enselman, Rachel, Dillon, Stacey R, Madden, Karen, Xu, Wenfeng, Parrish-Novak, Julia, Foster, Don, Lofton-Day, Cathy, Moore, Margaret, Littau, Alisa, Grossman, Angelika, Haugen, Harald, Foley, Kevin, Blumberg, Hal, Harrison, Kim, Kindsvogel, Wayne, Clegg, Christopher H
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Autoimmune Diseases - immunology
Autoimmune Diseases - metabolism
B-Cell Activating Factor
B-Cell Maturation Antigen
B-Lymphocytes - metabolism
BCMA protein
Biological and medical sciences
Cells
Cells, Cultured
COS Cells
Female
General aspects
Humans
Immune system
Immunoglobulin G - metabolism
Immunoglobulin M - metabolism
Immunopathology
Lupus Erythematosus, Systemic - immunology
Lupus Erythematosus, Systemic - metabolism
Lymphocyte Count
Medical sciences
Membrane Proteins - metabolism
Mice
Mice, Transgenic
Molecular Sequence Data
Pathology
Receptors, Antigen, B-Cell - immunology
Receptors, Antigen, B-Cell - metabolism
Receptors, Tumor Necrosis Factor - metabolism
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
T-Lymphocytes
TACI protein
Transmembrane Activator and CAML Interactor Protein
Tumor Necrosis Factor-alpha - metabolism
zTNF4 protein
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Summary: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) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. 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, TACI and BCMA, 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/35010115