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New receptor critical for BAFF-mediated B cell survival
Arthritis Research & Therapyvolume 3, Article number: 71704 (2001)
The TNF family member BAFF (also known as BLyS, TALL-1, THANK and zTHF4) is overexpressed in autoimmune diseases such as SLE and RA. Inhibition of BAFF function through recombinant receptor TACI-Ig has dramatic effects on the onset and progression of CIA in a mouse model of the disease (see Additional information ). Two receptors for BAFF, TACI and BCMA, have previously been described, both of which are also receptors for another TNF family member, APRIL. This paper describes the cloning of a unique BAFF receptor that does not bind APRIL and may mediate effects of BAFF on B-cell survival.
Initial studies of the BJAB B-cell line suggested the existence of a third BAFF receptor, since it bound high levels of BAFF although no or/low levels of TACI and BCMA were found. A novel BAFF receptor, BAFF-R, which was found to be specific for BAFF, was cloned from a BJAB library. The authors also generated a recombinant BAFF-R-Fc fusion protein, which inhibited BAFF binding to BJAB cells and inhibited BAFF-mediated co-stimulation of B-cell proliferation. BAFF-deficient mice have profound B-cell defects reminiscent of the A/WySnJ mouse strain, the authors examined BAFF-R expression in A/WySnJ mice. BAFF-R expressed in the A/WySnJ mice lacks exon 3, which encodes the intracellular signalling domain of BAFF-R; this defect presumably eradicates its function. Neither the TACI nor BCMA knockout mice have B-cell deficiencies similar to BAFF knockout mice, implicating BAFF-R as the major effector for BAFF-mediated B-cell survival. Additionally, APRIL and BAFF signalling through TACI and BCMA could not compensate for loss of BAFF-R, demonstrating its critical role in B-cell survival and homeostasis. BAFF-R and its deficiency in A/WySnJ have been reported by another group (see Additional information ), although they name the new receptor BLyS receptor 3.
BAFF-R is a suitable, specific receptor for BAFF, which may mediate the effects of TACI-Ig in mouse models of SLE and RA (see Additional information ). Given the inhibition of mouse CIA seen with TACI-Ig treatment, BAFF-R-Fc should also have clinical applications. In fact, it is presumed that TACI-Ig inhibition is through inhibition of BAFF and not APRIL, but BAFF-R-Fc could prove this. The current model of BAFF-BAFF-R function is that its primary function is in B-cell homeostasis, providing a signal to block cell death of mature B cells. In the A/WySnJ mice, the result is a severe block in B-cell development. In normal mice, blocking BAFF function through TACI-Ig results in a dramatic decrease in mature B cells (see Additional information ). In autoimmune disease, the functional consequence of blocking BAFF may be the elimination of autoreactive B-cell clones. Uncovering how BAFF-R functions and designing strategies to inhibit BAFF-R function could have direct clinical applications to autoimmune diseases.
Expression cloning, northern analysis, receptor-ligand associations
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