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Originally published in Science Express on 16 August 2001
Science 14 September 2001:
Vol. 293. no. 5537, pp. 2108 - 2111
DOI: 10.1126/science.1061965
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BAFF-R, a Newly Identified TNF Receptor That Specifically Interacts with BAFF

Jeffrey S. Thompson,1 Sarah A. Bixler,1 Fang Qian,1 Kalpit Vora,1* Martin L. Scott,1 Teresa G. Cachero,1 Catherine Hession,1 Pascal Schneider,2 Irene D. Sizing,1 Colleen Mullen,1 Kathy Strauch,1 Mohammad Zafari,1 Christopher D. Benjamin,1 Jurg Tschopp,2 Jeffrey L. Browning,1 Christine Ambrose1dagger

B cell homeostasis has been shown to critically depend on BAFF, the B cell activation factor from the tumor necrosis factor (TNF) family. Although BAFF is already known to bind two receptors, BCMA and TACI, we have identified a third receptor for BAFF that we have termed BAFF-R. BAFF-R binding appears to be highly specific for BAFF, suggesting a unique role for this ligand-receptor interaction. Consistent with this, the BAFF-R locus is disrupted in A/WySnJ mice, which display a B cell phenotype qualitatively similar to that of the BAFF-deficient mice. Thus, BAFF-R appears to be the principal receptor for BAFF-mediated mature B cell survival.

1 Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA.
2 The Institute of Biochemistry, University of Lausanne, CH-1066, Epalinges, Switzerland.
*   Present address: Department of Biologics Research, Merck & Co., 126 East Lincoln Avenue, RY 80Y-310, Rahway, NJ 07065, USA.

dagger    To whom correspondence should be addressed. E-mail: christine_ambrose{at}biogen.com

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J. Biol. Chem. 279, 44563-44572
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Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome.
A. J. Novak, D. M. Grote, M. Stenson, S. C. Ziesmer, T. E. Witzig, T. M. Habermann, B. Harder, K. M. Ristow, R. J. Bram, D. F. Jelinek, et al. (2004)
Blood 104, 2247-2253
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Rapid Response of Marginal Zone B Cells to Viral Particles.
D. Gatto, C. Ruedl, B. Odermatt, and M. F. Bachmann (2004)
J. Immunol. 173, 4308-4316
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Decreased Survival of B Cells of HIV-viremic Patients Mediated by Altered Expression of Receptors of the TNF Superfamily.
S. Moir, A. Malaspina, O. K. Pickeral, E. T. Donoghue, J. Vasquez, N. J. Miller, S. R. Krishnan, M. A. Planta, J. F. Turney, J. S. Justement, et al. (2004)
J. Exp. Med. 200, 587-600
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Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus.
M. Ramanujam, X. Wang, W. Huang, L. Schiffer, C. Grimaldi, A. Akkerman, B. Diamond, M. P. Madaio, and A. Davidson (2004)
J. Immunol. 173, 3524-3534
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Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus.
W Stohl, S Metyas, S-M Tan, G S Cheema, B Oamar, V Roschke, Y Wu, K P Baker, and D M Hilbert (2004)
Ann Rheum Dis 63, 1096-1103
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TNF Family Member B Cell-Activating Factor (BAFF) Receptor-Dependent and -Independent Roles for BAFF in B Cell Physiology.
Y. Sasaki, S. Casola, J. L. Kutok, K. Rajewsky, and M. Schmidt-Supprian (2004)
J. Immunol. 173, 2245-2252
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B Cell-Activating Factor Belonging to the TNF Family Acts through Separate Receptors to Support B Cell Survival and T Cell-Independent Antibody Formation.
S. Shulga-Morskaya, M. Dobles, M. E. Walsh, L. G. Ng, F. MacKay, S. P. Rao, S. L. Kalled, and M. L. Scott (2004)
J. Immunol. 173, 2331-2341
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Induction of p100 Processing by NF-{kappa}B-inducing Kinase Involves Docking I{kappa}B Kinase {alpha} (IKK{alpha}) to p100 and IKK{alpha}-mediated Phosphorylation.
G. Xiao, A. Fong, and S.-C. Sun (2004)
J. Biol. Chem. 279, 30099-30105
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B Cell-Activating Factor Belonging to the TNF Family (BAFF)-R Is the Principal BAFF Receptor Facilitating BAFF Costimulation of Circulating T and B Cells.
L. G. Ng, A. P. R. Sutherland, R. Newton, F. Qian, T. G. Cachero, M. L. Scott, J. S. Thompson, J. Wheway, T. Chtanova, J. Groom, et al. (2004)
J. Immunol. 173, 807-817
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A therapeutic role for BLyS antagonists.
W Stohl (2004)
Lupus 13, 317-322
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Engineering an APRIL-specific B Cell Maturation Antigen.
D. R. Patel, H. J. A. Wallweber, J. Yin, S. K. Shriver, S. A. Marsters, N. C. Gordon, M. A. Starovasnik, and R. F. Kelley (2004)
J. Biol. Chem. 279, 16727-16735
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BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.
J. Moreaux, E. Legouffe, E. Jourdan, P. Quittet, T. Reme, C. Lugagne, P. Moine, J.-F. Rossi, B. Klein, and K. Tarte (2004)
Blood 103, 3148-3157
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Impaired IgA class switching in APRIL-deficient mice.
E. Castigli, S. Scott, F. Dedeoglu, P. Bryce, H. Jabara, A. K. Bhan, E. Mizoguchi, and R. S. Geha (2004)
PNAS 101, 3903-3908
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BAFF/BLyS can potentiate B-cell selection with the B-cell coreceptor complex.
H. Hase, Y. Kanno, M. Kojima, K. Hasegawa, D. Sakurai, H. Kojima, N. Tsuchiya, K. Tokunaga, N. Masawa, M. Azuma, et al. (2004)
Blood 103, 2257-2265
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BAFF production by antigen-presenting cells provides T cell co-stimulation.
B. Huard, L. Arlettaz, C. Ambrose, V. Kindler, D. Mauri, E. Roosnek, J. Tschopp, P. Schneider, and L. E. French (2004)
Int. Immunol. 16, 467-475
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Lymphoma B Cells Evade Apoptosis through the TNF Family Members BAFF/BLyS and APRIL.
B. He, A. Chadburn, E. Jou, E. J. Schattner, D. M. Knowles, and A. Cerutti (2004)
J. Immunol. 172, 3268-3279
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APRIL-Deficient Mice Have Normal Immune System Development.
E. Varfolomeev, F. Kischkel, F. Martin, D. Seshasayee, H. Wang, D. Lawrence, C. Olsson, L. Tom, S. Erickson, D. French, et al. (2004)
Mol. Cell. Biol. 24, 997-1006
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Cutting Edge: BAFF Regulates CD21/35 and CD23 Expression Independent of Its B Cell Survival Function.
L. Gorelik, A. H. Cutler, G. Thill, S. D. Miklasz, D. E. Shea, C. Ambrose, S. A. Bixler, L. Su, M. L. Scott, and S. L. Kalled (2004)
J. Immunol. 172, 762-766
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Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway.
C. Kern, J.-F. Cornuel, C. Billard, R. Tang, D. Rouillard, V. Stenou, T. Defrance, F. Ajchenbaum-Cymbalista, P.-Y. Simonin, S. Feldblum, et al. (2004)
Blood 103, 679-688
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