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 mechani sms involving disregulated polyclonal B-cell activation, production of path ogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK)(1-5) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo (1,2,5). Here we identify two receptors for zTNF4 and demonstrate a relatio nship between zTNF4 and autoimmune disease. Transgenic animals overexpressi ng zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupu s erythaematosus (SLE) and expand a rare population of splenic B-1a lymphoc ytes. 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 T NF receptor family members, TACI(6) and BCMA(7,8), that bind zTNF4. Treatme nt of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the developm ent of proteinuria and prolongs survival of the animals. These findings dem onstrate the involvement of zTNF4 and its receptors in the development of S LE and identify TACI-Ig as a promising treatment of autoimmune disease in h umans.