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

Abstract

B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated 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-Ia 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.

Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis

“…Transgenic mice overexpressing BLyS develop symptoms characteristic of systemic lupus erythematosus (SLE). 4,6,7 Circulating BLyS is elevated in SLE model mice, NZB/W F1 and MRL-lpr/ lpr. 4 In addition, TACI-Ig treatment inhibits development of proteinurea in NZB/W F1 mice, and the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis (RA).…”

“…4,6,7 Circulating BLyS is elevated in SLE model mice, NZB/W F1 and MRL-lpr/ lpr. 4 In addition, TACI-Ig treatment inhibits development of proteinurea in NZB/W F1 mice, and the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis (RA). 4,11,22 Recently, increase of BLyS level was also reported in the serum or synovial fluid of human SLE, RA and Sjö gren's syndrome.…”

“…[1][2][3][4][5] BLyS is a potent B cell co-stimulator, and promotes B cell differentiation, proliferation and survival. 1,2,[6][7][8][9][10] In BLyS deficient mice, the number of B cells, serum IgG and IgM levels were decreased, and B cell development was blocked at the transitional T1 stage.…”

“…1,2,[6][7][8][9][10] In BLyS deficient mice, the number of B cells, serum IgG and IgM levels were decreased, and B cell development was blocked at the transitional T1 stage. 11 BLyS and a proliferation-inducing ligand (APRIL) bind to B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), 4,12,13 which belong to the tumor necrosis factor receptor superfamily and are mainly expressed in B cells. [14][15][16][17] The intracellular domains of BCMA and TACI associate with TNFreceptor-associated factors (TRAFs), leading to activation of NF-kB.…”

“…4 In addition, TACI-Ig treatment inhibits development of proteinurea in NZB/W F1 mice, and the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis (RA). 4,11,22 Recently, increase of BLyS level was also reported in the serum or synovial fluid of human SLE, RA and Sjö gren's syndrome. [23][24][25] Serum BLyS level was shown to be correlated with those of anti-dsDNA antibody and rheumatoid factor (RF), 24 although another study failed to show correlation with RF or with anti-Ro, anti-La with BLyS.…”