Autoimmune Disease

Targeting the Receptors

Science's STKE  02 May 2000:
Vol. 2000, Issue 30, pp. tw7
DOI: 10.1126/stke.2000.30.tw7

A member of the tumor necrosis factor (TNF) family, zTNF4, has been implicated in the development of autoimmune disease. Gross et al. show that transgenic mice expressing zTNF4 from a lymphoid-specific promoter show hallmark characteristics of systemic lupus erythematosus (SLE), a B cell autoimmune disease. The authors identified two receptors (TACI and BCMA) for zTNF4 by expression cloning. The two receptors were expressed on B cells and zTNF4 bound to each receptor with high affinity. Decoy receptors made from fusions between the extracellular domains of the two receptors and the Fc portion of human IgG1 inhibited binding and B cell activation by zTNF4 in vitro. These decoy receptors were also effective in prolonging the life-span and suppressing disease progression in NZBWF1 mice, which have elevated levels of circulating zTNF4 and develop spontaneous SLE. Thus, zTNF4 and these two receptors point to a new direction for developing treatments for autoimmune diseases. In the accompanying news and views by Ware, the use of decoy receptors in the treatment of several human diseases is discussed.

Gross, J.A., Johnston, J., Mudri, S., Enselman, R., Dillon, S.R., Madden, K., Xu, X., Parrish-Novak, J., Foster, D., Lofton-Day, C., Moore, M., Littau, A., Grossman, A., Haugen, H., Foley, K., Blumberg, H., Harrison, K., Kindsvogel, W., and Clegg, C.H. (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404: 995-999. [Online Journal]

Ware, C.F. (2000) Decoy receptors thwart B cells. Nature 404: 949-950. [Online Journal]