Enhanced selection of high affinity DNA-reactive B cells following cyclophosphamide treatment in mice.
A major goal for the treatment of patients with systemic lupus erythematosus 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 of cyclophosphamide on the selection of the re-emerging B cell repertoire in wild type mice and transgenic mice that express the H chain of an anti-DNA antibody. The reconstituting B cell repertoire in wild type mice contained an increased frequency of DNA-reactive B cells; in heavy chain transgenic mice, the reconstituting repertoire was characterized by an increased frequency of mature, high affinity DNA-reactive B cells and the mice expressed increased levels of serum anti-DNA antibodies. This coincided with a significant increase in serum levels of BAFF. Treatment of transgene-expressing mice with 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, not only is negative selection of high affinity DNA-reactive B cells impaired by increased BAFF, but also that B cells escaping negative selection are positively selected by autoantigen. There are significant implications for therapy.
Kawabata
Daisuke
D
Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Venkatesh
Jeganathan
J
Ramanujam
Meera
M
Davidson
Anne
A
Grimaldi
Christine M
CM
Diamond
Betty
B
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology*; D004247:DNA / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009500:Neutralization Tests; D013154:Spleen / Q000166:cytology / Q000187:drug effects*
D003520:Cyclophosphamide; D004247:DNA