Enhanced selection of high affinity DNA-reactive B cells following cyclophosphamide treatment (99.40)

Abstract

Abstract A major goal for the treatment of SLE patients with cytotoxic therapies is the induction of long term remission. There is, however, a paucity of information concerning the effects of these therapies on the reconstituting B cell repertoire. Since there is recent evidence suggesting that B cell lymphopenia might attenuate negative selection of autoreactive B cells, we elected to investigate the effects cyclophosphamide (CY) on the selection of the re-emerging B cell repertoire in transgenic mice that express the H chain of an anti-DNA antibody (R4A-Tg). The reconstituting B cell repertoire contained an increased frequency of mature, high affinity DNA-reactive B cells as determined by single cell PCR analysis, and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in levels of BAFF, a B cell survival factor. Treatment with BAFF-R-Ig, a BAFF blocking agent or with DNase, to reduce exposure to autoantigen, limited the expansion of high affinity DNA-reactive B cells during B cell reconstitution. These studies suggest that during B cell reconstitution, negative selection of high affinity DNA-reactive B cells is impaired by increased BAFF. B cells escaping negative selection are positively selected by autoantigen. BAFF blockade following treatment with B cell depleting agents may be useful for the successful long-term remission of SLE.